IMIDAZO[1,2-a]PYRIDINE SULFONAMIDES AS TRPM8 MODULATORS

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: 
     
       
         
         
             
             
         
       
     
     wherein Y, R 1 , R 2 , and are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

FIELD OF THE INVENTION

The present invention relates to imidazo[1,2-a]pyridine sulfonamidesthat act as modulators of the TRPM8 (transient receptor potentialmelastatin subfamily type 8) receptor. The present invention alsorelates to processes for the preparation of imidazo[1,2-a]pyridinesulfonamides and to their use in treating various diseases, syndromes,and disorders, including those that cause inflammatory pain, neuropathicpain, cardiovascular diseases aggravated by cold, pulmonary diseasesaggravated by cold, and combinations thereof.

BACKGROUND OF THE INVENTION

Transient receptor potential (TRP) channels are non-selective cationchannels that are activated by a variety of stimuli. Numerous members ofthe ion channel family have been identified to date, including thecold-menthol receptor, also called TRPM8 (McKemy D. D., et al., Nature2002, 416(6876), 52-58). Collectively, the TRP channels and relatedTRP-like receptors connote sensory responsivity to the entire continuumof thermal exposure, selectively responding to threshold temperaturesranging from noxious hot to noxious cold, as well as to certainchemicals that mimic these sensations. Specifically, TRPM8 may bestimulated by cool to cold temperatures as well as by chemical agentssuch as menthol and icilin, which may be responsible for the therapeuticcooling sensation that these agents provoke.

TRPM8 is located on primary nociceptive neurons (A-delta and C-fibers)and is also modulated by inflammation-mediated second messenger signals(Abe, J., et al., Neurosci Lett 2006, 397(1-2), 140-144; Premkumar, L.S., et al., J. Neurosci, 2005, 25(49), 11322-11329). The localization ofTRPM8 on both A-delta and C-fibers may provide a basis for abnormal coldsensitivity in pathologic conditions wherein these neurons are altered,resulting in pain, often of a burning nature (Kobayashi, K., et al., JComp Neurol, 2005, 493(4), 596-606; Roza, C., et al., Pain, 2006,120(1-2), 24-35; and Xing, H., et al., J Neurophysiol, 2006, 95(2),1221-30). Cold intolerance and paradoxical burning sensations induced bychemical or thermal cooling closely parallel symptoms seen in a widerange of clinical disorders and thus provide a strong rationale for thedevelopment of TRPM8 modulators as novel antihyperalgesic orantiallodynic agents. TRPM8 is also known to be expressed in the brain,lung, bladder, gastrointestinal tract, blood vessels, prostate andimmune cells, thereby providing the possibility for therapeuticmodulation in a wide range of maladies.

International patent application WO 2006/040136 A1 from Bayer HealthcareAG purportedly describes substituted 4-benzyloxy-phenylmethylamidederivatives as cold menthol receptor-1 (CMR-1) antagonists for thetreatment of urological disorders. International patent application WO2006/040103 A1 from Bayer Healthcare AG purportedly describes methodsand pharmaceutical compositions for treatment and/or prophylaxis ofrespiratory diseases or disorders.

International patent applications WO 2007/017092A1, WO 2007/017093A1 andWO 2007/017094A1, from Bayer Healthcare AG, purportedly describebenzyloxyphenylmethyl carbamate, substituted 2-benzyloxybenzoic acidamide and substituted 4-benzyloxybenzoic acid amide derivatives for thetreatment of diseases associated with the cold menthol receptor (CMR),a.k.a. TRPM8.

There is a need in the art for TRPM8 modulators that can be used totreat a disease, syndrome, or condition in a mammal in which thedisease, syndrome, or condition is affected by the modulation of TRPM8receptors, such as pain, the diseases that lead to such pain, andpulmonary or vascular dysfunction.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I)

wherein

Y is selected from the group consisting of hydrogen, bromo, chloro, C₃₋₆cycloalkyl, and C₁₋₆ alkyl;

R¹ is

i) C₁₋₆alkyl wherein C₁₋₆alkyl is unsubstituted or substituted with onesubstituent that is C₃₋₆cycloalkyl or trifluoromethyl; or

ii) phenylmethyl wherein the phenyl ring is unsubstituted or substitutedwith one to three substituents each of which is independently selectedfrom the group consisting of chloro, fluoro, bromo, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethoxy, C₁₋₄alkoxycarbonyl, C₁₋₃alkylthio,trifluoromethylthio, cyano, trifluoromethyl, C₁₋₃ alkylsulfonyl,trifluoromethylsulfonyl, and C₁₋₃ alkylcarbonyl; with the proviso thatnot more than two of the substituents are selected from the groupconsisting of C₁₋₄alkoxy, trifluoromethoxy, C₁₋₄ alkoxycarbonyl,C₁₋₃alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C₁₋₃alkylsulfonyl, trifluoromethylsulfonyl, and C₁₋₃ alkylcarbonyl;

R² is one substituent selected from the group consisting of hydrogen,C₁₋₄ alkyl, chloro, fluoro, and trifluoromethyl; with the proviso thatR² is other than 5-trifluoromethyl;

R³ is

i) C₁₋₃alkyl wherein C₁₋₃alkyl is unsubstituted or substituted with onesubstituent selected from the group consisting of carboxy,methoxycarbonyl, trifluoromethyl, and methoxy;

ii) —(CH₂)₂NR^(A)R^(B) wherein R^(A) and R^(B) are each independentlyC₁₋₆alkyl; or, R^(A) and R^(B) are taken together with the nitrogen atomto which they are attached to form piperidin-1-yl;

iii) phenyl substituted at the 4-position with pyrazolyl; wherein thepoint of attachment of the pyrazole is through a nitrogen heteroatom;

iv) phenyl wherein phenyl is unsubstituted or substituted with one ortwo substituents each of which is independently selected from the groupconsisting of chloro, fluoro, bromo, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,carboxy, and C₁₋₃alkyl; or

v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;

provided that a compound of Formula (I) is other than the compoundwherein Y is methyl, R¹ is 4-trifluoromethoxyphenylmethyl, R² is7-trifluoromethyl, and R³ is phenyl; or the compound wherein Y ishydrogen, R¹ is 4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³is 4-carboxyphenyl; and enantiomers, diastereomers, solvates, andpharmaceutically acceptable salt forms thereof.

The present invention also provides a pharmaceutical compositioncomprising, consisting of and/or consisting essentially of apharmaceutically acceptable carrier, a pharmaceutically acceptableexcipient, and/or a pharmaceutically acceptable diluent and a compoundof Formula (I) or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical compositioncomprising, consisting of, and/or consisting essentially of admixing acompound of Formula (I) and a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient, and/or a pharmaceuticallyacceptable diluent.

The present invention further provides methods for treating orameliorating a TRPM8-modulated disorder in a subject, including a mammaland/or human in which the disease, syndrome, or condition is affected bythe modulation of TRPM8 receptors, such as pain, the diseases that leadto such pain, and pulmonary or vascular dysfunction using a compound ofFormula (I). In particular, the methods of the present invention aredirected to treating or ameliorating a TRPM8 receptor-modulated disorderincluding inflammatory pain, neuropathic pain, cardiovascular diseasesaggravated by cold, and pulmonary diseases aggravated by cold, using acompound of Formula (I).

The present invention also is also directed to the use of any of thecompounds described herein in the preparation of a medicament whereinthe medicament is prepared for treating a disease or condition selectedfrom the group consisting of inflammatory pain, neuropathic pain,cardiovascular disease aggravated by cold, and pulmonary diseaseaggravated by cold, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term “independently” refers to thesituation where when more than one substituent is possible, thesubstituents may be the same or different from each other.

The term “alkyl” whether used alone or as part of a substituent group,refers to straight and branched carbon chains having 1 to 8 carbonatoms. Therefore, designated numbers of carbon atoms (e.g., C₁₋₈) referindependently to the number of carbon atoms in an alkyl moiety or to thealkyl portion of a larger alkyl-containing substituent. In substituentgroups with multiple alkyl groups such as, (C₁₋₆alkyl)₂amino-, theC₁₋₆alkyl groups of the dialkylamino may be the same or different.

The term “alkoxy” refers to an —O-alkyl group, wherein the term “alkyl”is as defined above.

The terms “alkenyl” and “alkynyl” refer to straight and branched carbonchains having 2 to 8 carbon atoms, wherein an alkenyl chain contains atleast one double bond and an alkynyl chain contains at least one triplebond.

The term “cycloalkyl” refers to saturated or partially saturated,monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms.Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and adamantyl.

The term “benzo-fused cycloalkyl” refers to a 5- to 8-memberedmonocyclic cycloalkyl ring fused to a benzene ring. The carbon atom ringmembers that form the cycloalkyl ring may be fully saturated orpartially saturated.

The term “heterocyclyl” refers to a nonaromatic monocyclic or bicyclicring system having 3 to 10 ring members that include at least 1 carbonatom and from 1 to 4 heteroatoms independently selected from N, O, andS. Included within the term heterocyclyl is a nonaromatic cyclic ring of5 to 7 members in which 1 to 2 members are N, or a nonaromatic cyclicring of 5 to 7 members in which 0, 1 or 2 members are N and up to 2members are O or S and at least one member must be either N, O, or S;wherein, optionally, the ring contains 0 to 1 unsaturated bonds, and,optionally, when the ring is of 6 or 7 members, it contains up to 2unsaturated bonds. The carbon atom ring members that form a heterocyclering may be fully saturated or partially saturated. The term“heterocyclyl” also includes two 5 membered monocyclic heterocycloalkylgroups bridged to form a bicyclic ring. Such groups are not consideredto be fully aromatic and are not referred to as heteroaryl groups. Whena heterocycle is bicyclic, both rings of the heterocycle arenon-aromatic and at least one of the rings contains a heteroatom ringmember. Examples of heterocycle groups include, and are not limited to,pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl),pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unlessotherwise noted, the heterocycle is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “benzo-fused heterocyclyl” refers to a 5 to 7 memberedmonocyclic heterocycle ring fused to a benzene ring. The heterocyclering contains carbon atoms and from 1 to 4 heteroatoms independentlyselected from N, O, and S. The carbon atom ring members that form theheterocycle ring may be fully saturated or partially saturated. Unlessotherwise noted, benzo-fused heterocycle ring is attached to its pendantgroup at a carbon atom of the benzene ring.

The term “aryl” refers to an unsaturated, aromatic monocyclic orbicyclic ring of 6 to 10 carbon members. Examples of aryl rings includephenyl and naphthalenyl.

The term “heteroaryl” refers to an aromatic monocyclic or bicyclicaromatic ring system having 5 to 10 ring members and which containscarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O, and S. Included within the term heteroaryl arearomatic rings of 5 or 6 members wherein the ring consists of carbonatoms and has at least one heteroatom member. Suitable heteroatomsinclude nitrogen, oxygen, and sulfur. In the case of 5 membered rings,the heteroaryl ring preferably contains one member of nitrogen, oxygenor sulfur and, in addition, up to 3 additional nitrogens. In the case of6 membered rings, the heteroaryl ring preferably contains from 1 to 3nitrogen atoms. For the case wherein the 6 membered ring has 3nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroarylgroups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl and quinazolinyl. Unlessotherwise noted, the heteroaryl is attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine atoms.

The term “formyl” refers to the group —C(═O)H.

The term “oxo” refers to the group (═O).

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., arylalkyl, alkylamino) the nameis to be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)refer independently to the number of carbon atoms in an alkyl moiety, anaryl moiety, or in the alkyl portion of a larger substituent in whichalkyl appears as its prefix root. For alkyl and alkoxy substituents, thedesignated number of carbon atoms includes all of the independentmembers included within a given range specified. For example C₁₋₆ alkylwould include methyl, ethyl, propyl, butyl, pentyl and hexylindividually as well as sub-combinations thereof (e.g., C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₂₋₆, C₃₋₆, C₄₋₆, C₅₋₆, C₂₋₅, etc.).

In general, under standard nomenclature rules used throughout thisdisclosure, the terminal portion of the designated side chain isdescribed first followed by the adjacent functionality toward the pointof attachment. Thus, for example, a “C₁-C₆ alkylcarbonyl” substituentrefers to a group of the formula:

Unless otherwise noted, for the compounds of Formula (I), the R²substituent shall be denoted as bound to the 5-, 6-, 7-, or 8-position,as defined by the following numbering convention:

Unless otherwise noted, it is intended that the definition of anysubstituent or variable at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. It isunderstood that substituents and substitution patterns on the compoundsof Formula (I) can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be readilysynthesized by techniques known in the art as well as those methods setforth herein.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who has been the object of treatment, observation orexperiment.

The term “therapeutically effective amount” refers to an amount of anactive compound or pharmaceutical agent, including a compound of thepresent invention, which elicits the biological or medicinal response ina tissue system, animal or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includesalleviation or partial alleviation of the symptoms of the disease,syndrome, condition, or disorder being treated.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “antagonist” is used to refer to a compound capable ofproducing, depending on the circumstance, a functional antagonism of theTRPM8 ion channel, including, but not limited to, competitiveantagonists, non-competitive antagonists, desensitizing agonists, andpartial agonists.

The term “agonist” is used to refer to a compound that is capable offunctionally activating the TRPM8 ion channel, including but not limitedto full agonists, partial agonists, positive modulators, sensitizingagonists, and desensitizing agonists, whether they act orthosterically(i.e., via the menthol/icilin site) or allosterically.

As used herein, “inflammatory hypersensitivity” is used to refer to acondition that is characterized by one or more hallmarks ofinflammation, including edema, erythema, hyperthermia and pain, and/orby an exaggerated physiologic or pathophysiologic response to one ormore than one type of stimulation, including thermal, mechanical, and/orchemical stimulation.

The term “TRPM8-modulated” is used to refer to the condition of beingaffected by the modulation of the TRPM8 receptor, including the state ofbeing mediated by the TRPM8 receptor.

An embodiment of the invention is a method of treating or preventing atleast one of the following diseases, syndromes, and conditions selectedfrom the group consisting of migraine, post herpetic neuralgia, posttraumatic neuralgia, post chemotherapy neuralgia, complex regional painsyndrome I and II (CRPS I/II), fibromyalgia, inflammatory bowel disease,pruritis, asthma, chronic obstructive pulmonary disease, toothache, bonepain and pyresis in a subject, which method comprises, consists of,and/or consists essentially of administering to the subject, includingan animal, a mammal, and a human in need of such treatment orprevention, a therapeutically effective amount of a TRPM8 antagonistthat is a compound of Formula (I).

Another embodiment of the invention is a method of treating orpreventing at least one of the following diseases, syndromes, andconditions selected from hypertension, peripheral vascular disease,Raynaud's disease, reperfusion injury or frostbite in a subject, whichmethod comprises administering to the subject, including an animal, amammal, and a human in need of such treatment or prevention atherapeutically effective amount of a TRPM8 antagonist that is acompound of Formula (I).

A further embodiment of the invention is a method of acceleratingpost-anesthetic recovery or post-hypothermia recovery in a subject,including an animal, a mammal, and a human, which method comprisesadministering to the subject, including an animal, a mammal, and a humanin need of such accelerated recovery, a therapeutically effective amountof a TRPM8 antagonist that is a compound of Formula (I).

An embodiment of the present invention is directed to a compound ofFormula (I)

wherein

-   a) Y is selected from the group consisting of hydrogen, bromo,    chloro, cyclopropyl, and C₁₋₄ alkyl;-   b) Y is selected from the group consisting of hydrogen, bromo,    chloro, cyclopropyl, methyl, ethyl, and isopropyl;-   c) R¹ is    -   i) C₁₋₆alkyl substituted with one substituent that is        C₃₋₆cycloalkyl or trifluoromethyl; or    -   ii) phenylmethyl wherein the phenyl ring is unsubstituted or        substituted with one to three substituents each of which is        independently selected from the group consisting of fluoro,        chloro, trifluoromethoxy, and trifluoromethyl; with the proviso        that not more than two of the substituents are trifluoromethoxy        or trifluoromethyl;-   d) R¹ is    -   i) C₁₋₆alkyl substituted with one substituent that is        cyclopropyl or trifluoromethyl; or    -   ii) phenylmethyl wherein the phenyl ring is substituted at the        3- or 4-positions with one to two substituents each of which is        independently selected from the group consisting of fluoro,        chloro, trifluoromethoxy, and trifluoromethyl;-   e) R¹ is    -   -   i) C₁₋₄alkyl substituted with one substituent that is            cyclopropyl or trifluoromethyl; or        -   ii) phenylmethyl wherein the phenyl ring is substituted at            the 3- or 4-positions with one to two substituents each of            which is independently selected from the group consisting of            fluoro, chloro, trifluoromethoxy, and trifluoromethyl;-   f) R² is one substituent selected from the group consisting of    hydrogen, methyl, chloro, fluoro, and trifluoromethyl; with the    proviso that R² is other than 5-trifluoromethyl;-   g) R² is one substituent selected from the group consisting of    hydrogen, methyl, chloro, and trifluoromethyl; with the proviso that    R² is other than 5-trifluoromethyl;-   h) R³ is    -   i) unsubstituted C₁₋₃alkyl;    -   ii) —(CH₂)₂NR^(A)R^(B) wherein R^(A) and R^(B) are each        independently C₁₋₆alkyl; or, R^(A) and R^(B) are taken together        with the nitrogen atom to which they are attached to form        piperidin-1-yl;    -   iii) phenyl substituted at the 4-position with pyrazol-1-yl;    -   iv) phenyl wherein phenyl is unsubstituted or substituted with        one substituent selected from the group consisting of fluoro,        bromo, C₁₋₄alkoxycarbonyl, and carboxy; or    -   v) pyridin-3-yl substituted at the 6-position with        morpholin-4-yl;-   i) R³ is    -   i) unsubstituted C₁₋₃alkyl;    -   ii) —(CH₂)₂NR^(A)R^(B) wherein R^(A) and R^(B) are each        independently C₁₋₆alkyl;    -   iii) phenyl substituted at the 4-position with pyrazol-1-yl;    -   iv) phenyl wherein phenyl is unsubstituted or substituted with        one or two substituents each of which is independently selected        from the group consisting of fluoro, bromo, methoxycarbonyl, and        carboxy; or    -   v) pyridin-3-yl substituted at the 6-position with        morpholin-4-yl;-   j) R³ is    -   i) methyl;    -   ii) phenyl substituted at the 4-position with pyrazol-1-yl;    -   iii) phenyl wherein phenyl is unsubstituted or substituted at        the 4-position with one substituent selected from the group        consisting of fluoro, bromo, methoxycarbonyl, and carboxy; or    -   iv) pyridin-3-yl substituted at the 6-position with        morpholin-4-yl;        and any combination of embodiments a) through j) above, provided        that it is understood that combinations in which different        embodiments of the same substituent would be combined are        excluded;        provided that a compound of Formula (I) is other than

the compound wherein Y is methyl, R¹ is 4-trifluoromethoxyphenylmethyl,R² is 7-trifluoromethyl, and R³ is phenyl; or the compound wherein Y ishydrogen, R¹ is 4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³is 4-carboxyphenyl; and enantiomers, diastereomers, solvates andpharmaceutically acceptable salts thereof

One embodiment of the present invention is directed to a compound ofFormula (I)

wherein

Y is selected from the group consisting of hydrogen, bromo, chloro,cyclopropyl, and C₁₋₄ alkyl;

R¹ is

-   i) C₁₋₆alkyl substituted with one substituent that is C₃₋₆cycloalkyl    or trifluoromethyl; or-   ii) phenylmethyl wherein the phenyl ring is unsubstituted or    substituted with one to three substituents each of which is    independently selected from the group consisting of fluoro, chloro,    trifluoromethoxy, and trifluoromethyl; with the proviso that not    more than two of the substituents are trifluoromethoxy or    trifluoromethyl;

R² is one substituent selected from the group consisting of hydrogen,methyl, chloro, fluoro, and trifluoromethyl; with the proviso that R² isother than 5-trifluoromethyl;

R³ is

-   i) unsubstituted C₁₋₃alkyl-   ii) —(CH₂)₂NR^(A)R^(B) wherein R^(A) and R^(B) are each    independently C₁₋₆alkyl; or, R^(A) and R^(B) are taken together with    the nitrogen atom to which they are attached to form piperidin-1-yl;    -   wherein R^(A) and R^(B) are each independently C₁₋₆alkyl; or,        R^(A) and R^(B) are taken together with the nitrogen atom to        which they are attached to form piperidin-1-yl, and said        piperidin-1-yl is unsubstituted or substituted at the 4-position        with phenyl;-   iii) phenyl substituted at the 4-position with pyrazol-1-yl;-   iv) phenyl wherein phenyl is unsubstituted or substituted with one    substituent selected from the group consisting of fluoro, bromo,    C₁₋₄alkoxycarbonyl, and carboxy; or-   v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;    provided that a compound of Formula (I) is other than

the compound wherein Y is methyl, R¹ is 4-trifluoromethoxyphenylmethyl,R² is 7-trifluoromethyl, and R³ is phenyl; or the compound wherein Y ishydrogen, R¹ is 4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³is 4-carboxyphenyl; and enantiomers, diastereomers, solvates andpharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to a compound ofFormula (I)

wherein

Y is selected from the group consisting of hydrogen, bromo, chloro,cyclopropyl, methyl, ethyl, and isopropyl;

R¹ is

-   i) C₁₋₆alkyl substituted with one substituent that is cyclopropyl or    trifluoromethyl; or-   ii) phenylmethyl wherein the phenyl ring is substituted at the 3- or    4-positions with one to two substituents each of which is    independently selected from the group consisting of fluoro, chloro,    trifluoromethoxy, and trifluoromethyl;

R² is one substituent selected from the group consisting of hydrogen,methyl, chloro, and trifluoromethyl; with the proviso that R² is otherthan 5-trifluoromethyl;

R³ is

-   i) unsubstituted C₁₋₃alkyl;-   ii) —(CH₂)₂NR^(A)R^(B) wherein R^(A) and R^(B) are each    independently C₁₋₆alkyl;-   iii) phenyl substituted at the 4-position with pyrazol-1-yl;-   iv) phenyl wherein phenyl is unsubstituted or substituted with one    or two substituents each of which is independently selected from the    group consisting of fluoro, bromo, methoxycarbonyl, and carboxy; or-   v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;    provided that a compound of Formula (I) is other than

the compound wherein Y is methyl, R¹ is 4-trifluoromethoxyphenylmethyl,R² is 7-trifluoromethyl, and R³ is phenyl; or the compound wherein Y ishydrogen, R¹ is 4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³is 4-carboxyphenyl; and enantiomers, diastereomers, solvates andpharmaceutically acceptable salts thereof

Another embodiment of the present invention is directed to a compound ofFormula (I)

wherein

Y is selected from the group consisting of hydrogen, bromo, chloro,cyclopropyl, methyl, ethyl, and isopropyl;

R¹ is

-   i) C₁₋₄alkyl substituted with one substituent that is cyclopropyl or    trifluoromethyl; or-   ii) phenylmethyl wherein the phenyl ring is substituted at the 3- or    4-positions with one to two substituents each of which is    independently selected from the group consisting of fluoro, chloro,    trifluoromethoxy, and trifluoromethyl;

R² is one substituent selected from the group consisting of hydrogen,methyl, chloro, and trifluoromethyl; with the proviso that R² is otherthan 5-trifluoromethyl;

R³ is

-   i) methyl;-   ii) phenyl substituted at the 4-position with pyrazol-1-yl;-   iii) phenyl wherein phenyl is unsubstituted or substituted at the    4-position with one substituent selected from the group consisting    of fluoro, bromo, methoxycarbonyl, and carboxy; or-   iv) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;    provided that a compound of Formula (I) is other than

the compound wherein Y is methyl, R¹ is 4-trifluoromethoxyphenylmethyl,R² is 7-trifluoromethyl, and R³ is phenyl; or the compound wherein Y ishydrogen, R¹ is 4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³is 4-carboxyphenyl; and enantiomers, diastereomers, solvates andpharmaceutically acceptable salts thereof.

A further embodiment of the present invention is directed to a compoundof Formula (I)

selected from the group consisting of

-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is bromo, R¹ is    4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is methyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is bromo, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is methyl;-   the compound wherein Y is bromo, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-carboxyphenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-fluorophenyl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-fluorophenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is hydrogen, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is hydrogen, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 7-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 7-chloro, and R³ is    phenyl;-   the compound wherein Y is chloro, R¹ is 4-fluorophenylmethyl, R² is    6-chloro, and R³ is phenyl;-   the compound wherein Y is chloro, R¹ is phenylmethyl, R² is    6-chloro, and R³ is phenyl;-   the compound wherein Y is chloro, R¹ is 3,4-difluorophenylmethyl, R²    is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-fluoro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-fluoro, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-fluoro, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-fluoro, and R³ is methyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-fluoro, and R³ is    methyl;-   the compound wherein Y is hydrogen, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is bromo, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 7-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 7-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 7-methyl, and R³ is    phenyl;-   the compound wherein Y is chloro, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 8-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 8-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 8-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethylphenylmethyl, R² is 8-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-trifluoromethylphenylmethyl, R² is 8-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 8-methyl, and R³ is    methyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 7-methyl, and R³ is    4-bromophenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-chloro-4-fluorophenylmethyl, R² is 6-chloro, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 5-methyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 5-methyl, and R³ is    phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 5-methyl, and R³ is    phenyl;-   the compound wherein Y is isopropyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is isopropyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is isopropyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is isopropyl, R¹ is    4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is isopropyl, R¹ is    3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 8-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 8-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 8-trifluoromethyl, and R³ is    phenyl;-   the compound wherein Y is ethyl, R¹ is    4-trifluoromethylphenylmethyl, R² is 8-trifluoromethyl, and R³ is    phenyl;-   the compound wherein Y is ethyl, R¹ is    3-trifluoromethylphenylmethyl, R² is 8-trifluoromethyl, and R³ is    phenyl;-   the compound wherein Y is chloro, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-trifluoromethyl, and R³ is    phenyl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is 2-cyclopropyl-ethyl, R² is    8-trifluoromethyl, and R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is 4-trifluoromethyl-butyl, R²    is 8-trifluoromethyl, and R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is cyclopropylmethyl, R² is    8-trifluoromethyl, and R³ is phenyl;-   the compound wherein Y is ethyl, R¹ is 2-trifluoromethyl-ethyl, R²    is 8-trifluoromethyl, and R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 7-methyl, and R³ is    4-fluorophenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-methyl, and R³ is    4-fluorophenyl;-   the compound wherein Y is cyclopropyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is cyclopropyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    phenyl;-   the compound wherein Y is cyclopropyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is cyclopropyl, R¹ is    4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is cyclopropyl, R¹ is    3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is phenyl;-   the compound wherein Y is chloro, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is ethyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 5-methyl, and R³ is    phenyl;-   the compound wherein Y is ethyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is ethyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    phenyl;-   the compound wherein Y is bromo, R¹ is phenylmethyl, R² is hydrogen,    and R³ is 6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is bromo, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is ethyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is ethyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is ethyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is chloro, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is chloro, R¹ is    3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    6-(morpholin-4-yl)-pyridin-3-yl;-   the compound wherein Y is chloro, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is chloro, R¹ is    3-trifluoromethylphenylmethyl, R² is hydrogen, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 7-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 7-trifluoromethyl, and    R³ is phenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is methyl, R¹ is    3-fluoro-4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-(1H-pyrazol-1-yl)phenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 7-trifluoromethyl, and R³ is    2-(di-isobutylamino)ethyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-carboxyphenyl sodium salt-phenyl;-   the compound wherein Y is isopropyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is isopropyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-carboxyphenyl sodium salt;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is 3,4-difluorophenylmethyl, R²    is 6-chloro, and R³ is 4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-chloro, and R³ is    4-carboxyphenyl;-   the compound wherein Y is methyl, R¹ is 3,4-difluorophenylmethyl, R²    is 6-chloro, and R³ is 4-carboxyphenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-chloro, and R³ is    4-carboxyphenyl;-   the compound wherein Y is chloro, R¹ is    4-trifluoromethoxyphenylmethyl, R² is hydrogen, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 8-methyl, and R³ is    4-carboxyphenyl sodium salt;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-fluoro, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-fluoro, and R³ is    4-methoxycarbonylphenyl;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 6-fluoro, and R³ is    4-carboxyphenyl sodium salt;-   the compound wherein Y is methyl, R¹ is    4-fluoro-3-trifluoromethylphenylmethyl, R² is 6-fluoro, and R³ is    4-carboxyphenyl sodium salt;-   the compound wherein Y is methyl, R¹ is    4-trifluoromethoxyphenylmethyl, R² is 7-fluoro, and R³ is    4-carboxyphenyl sodium salt;    and pharmaceutically acceptable salt forms thereof.

For use in medicine, salts of compounds of Formula (I) refer tonon-toxic “pharmaceutically acceptable salts.” Other salts may, however,be useful in the preparation of compounds of Formula (I) or of theirpharmaceutically acceptable salts thereof. Suitable pharmaceuticallyacceptable salts of compounds of Formula (I) include acid addition saltswhich can, for example, be formed by mixing a solution of the compoundwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of Formula (I)carry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include alkali metal salts, such as sodium or potassiumsalts; alkaline earth metal salts, such as calcium or magnesium salts;and salts formed with suitable organic ligands, such as quaternaryammonium salts. Thus, representative pharmaceutically acceptable saltsinclude acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids that may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, acidsincluding acetic acid, 2,2-dichloroacetic acid, acylated amino acids,adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid.

Representative bases that may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

Embodiments of the present invention include prodrugs of compounds ofFormula (I). In general, such prodrugs will be functional derivatives ofthe compounds that are readily convertible in vivo into the requiredcompound. Thus, in the methods of treating or preventing embodiments ofthe present invention, the term “administering” encompasses thetreatment or prevention of the various diseases, conditions, syndromesand disorders described with the compound specifically disclosed or witha compound that may not be specifically disclosed, but which converts tothe specified compound in vivo after administration to a patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985. Where the compounds according toembodiments of this invention have at least one chiral center, they mayaccordingly exist as enantiomers.

Where the compounds possess two or more chiral centers, they mayadditionally exist as diastereomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofthe present invention. Furthermore, some of the crystalline forms forthe compounds may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compoundsmay form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention. The skilled artisan will understand thatthe term “compound” as used herein, is meant to include solvatedcompounds of Formula (I).

Where the processes for the preparation of the compounds according tocertain embodiments of the invention give rise to a mixture ofstereoisomers, these isomers may be separated by conventional techniquessuch as preparative chromatography. The compounds may be prepared inracemic form, or individual enantiomers may be prepared either byenantiospecific synthesis or by resolution. The compounds may, forexample, be resolved into their component enantiomers by standardtechniques, such as the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acidfollowed by fractional crystallization and regeneration of the freebase. The compounds may also be resolved by formation of diastereomericesters or amides, followed by chromatographic separation and removal ofthe chiral auxiliary. Alternatively, the compounds may be resolved usinga chiral HPLC column.

One embodiment of the present invention is directed to a composition,including a pharmaceutical composition, comprising, consisting of,and/or consisting essentially of the (+)-enantiomer of a compound ofFormula (I) wherein said composition is substantially free from the(−)-isomer of said compound. In the present context, substantially freemeans less than about 25%, preferably less than about 10%, morepreferably less than about 5%, even more preferably less than about 2%and even more preferably less than about 1% of the (−)-isomer calculatedas

${{\% ( + )} - {enantiomer}} = {\frac{\begin{pmatrix}{{{mass}( + )} -} \\{enantiomer}\end{pmatrix}}{\begin{pmatrix}{{{mass}( + )} -} \\{enantiomer}\end{pmatrix} + \begin{pmatrix}{{{mass}( - )} -} \\{enantiomer}\end{pmatrix}} \times 100}$

Another embodiment of the present invention is a composition, includinga pharmaceutical composition, comprising, consisting of, and consistingessentially of the (−)-enantiomer of a compound of Formula (I) whereinsaid composition is substantially free from the (+)-isomer of saidcompound. In the present context, substantially free from means lessthan about 25%, preferably less than about 10%, more preferably lessthan about 5%, even more preferably less than about 2% and even morepreferably less than about 1% of the (+)-isomer calculated as

${{\% ( + )} - {enantiomer}} = {\frac{\begin{pmatrix}{{{mass}( + )} -} \\{enantiomer}\end{pmatrix}}{\begin{pmatrix}{{{mass}( + )} -} \\{enantiomer}\end{pmatrix} + \begin{pmatrix}{{{mass}( - )} -} \\{enantiomer}\end{pmatrix}} \times 100}$

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1999. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient, and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds ofFormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of Formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a white waxor white soft paraffin base together with any stabilizers andpreservatives as may be required. An alternative means of administrationincludes transdermal administration by using a skin or transdermalpatch. The pharmaceutical compositions of the present invention (as wellas the compounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of Formula (I) as the active ingredient canbe prepared by mixing the compound(s) with a pharmaceutically acceptablecarrier, a pharmaceutically acceptable diluent, and/or apharmaceutically acceptable excipient according to conventionalpharmaceutical compounding techniques. The carrier, excipient, anddiluent may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral, etc.). Thus for liquidoral preparations, such as suspensions, syrups, elixirs and solutions,suitable carriers, excipients and diluents include water, glycols, oils,alcohols, flavoring agents, preservatives, stabilizers, coloring agentsand the like; for solid oral preparations, such as powders, capsules andtablets, suitable carriers, excipients and diluents include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances, such as sugars, or beenterically-coated so as to modulate the major site of absorption anddisintegration. For parenteral administration, the carrier, excipientand diluent will usually include sterile water, and other ingredientsmay be added to increase solubility and preservation of the composition.Injectable suspensions or solutions may also be prepared utilizingaqueous carriers along with appropriate additives, such as solubilizersand preservatives.

A therapeutically effective amount of a compound of Formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or,more particularly, from about 10 mg to about 500 mg of active ingredientin a regimen of about 1 to 4 times per day for an average (70 kg) human;although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the diseases, syndromes, conditions, and disordersbeing treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 0.01, about 10, about50, about 100, about 150, about 200, about 250, and about 500 milligramsof the inventive compound as the active ingredient.

Advantageously, a compound of Formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily. Optimal dosages of acompound of Formula (I) to be administered may be readily determined andwill vary with the particular compound used, the mode of administration,the strength of the preparation, and the advancement of the disease,syndrome, condition, or disorder. In addition, factors associated withthe particular subject being treated, including subject age, weight,diet and time of administration, will result in the need to adjust thedose to achieve an appropriate therapeutic level. The above dosages arethus exemplary of the average case. There can be, of course, individualinstances wherein higher or lower dosage ranges are merited, and suchare within the scope of this invention.

Compounds of Formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound ofFormula (I) is required for a subject in need thereof.

As agonists of the TRPM8 ion channel, the compounds of Formula (I) areuseful in methods for treating and preventing a disease, a syndrome, acondition, or a disorder in a subject, including an animal, a mammal anda human in which the disease, the syndrome, the condition, or thedisorder is affected by the modulation of TRPM8 receptors. Such methodscomprise, consist of, and consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of acompound, salt, or solvate of Formula (I). In particular, the compoundsof Formula (I) are useful for preventing or treating prostate cancer.

As antagonists of the TRPM8 ion channel, the compounds of Formula (I)are useful in methods for treating and preventing a disease, a syndrome,a condition, or a disorder in a subject, including an animal, a mammaland a human in which the disease, the syndrome, the condition, or thedisorder is affected by the modulation of TRPM8 receptors. Such methodscomprise, consist of, and consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of acompound, salt, or solvate of Formula (I). In particular, the compoundsof Formula (I) are useful for preventing or treating pain, or diseases,syndromes, conditions, or disorders causing such pain, or pulmonary orvascular dysfunction. More particularly, the compounds of Formula (I)are useful for preventing or treating inflammatory pain, inflammatoryhypersensitivity conditions, neuropathic pain, anxiety, depression, andcardiovascular disease aggravated by cold, including peripheral vasculardisease, vascular hypertension, pulmonary hypertension, Raynaud'sdisease, and coronary artery disease, by administering to a subject inneed thereof a therapeutically effective amount of a compound of Formula(I).

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state including inflammatory boweldisease, visceral pain, migraine, post-operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, sinus headache, tension headache, orarachnoiditis. One type of inflammatory pain is inflammatoryhyperalgesia, which can be further distinguished as inflammatory somatichyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatichyperalgesia can be characterized by the presence of an inflammatoryhyperalgesic state in which a hypersensitivity to thermal, mechanicaland/or chemical stimuli exists. Inflammatory visceral hyperalgesia canalso be characterized by the presence of an inflammatory hyperalgesicstate, in which an enhanced visceral irritability exists.

Examples of inflammatory hyperalgesia include a disease, syndrome,condition, disorder, or pain state including inflammation,osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominalpain, musculoskeletal diseases, skin diseases, post operative pain,headaches, toothache, burn, sunburn, insect sting, neurogenic bladder,urinary incontinence, interstitial cystitis, urinary tract infection,cough, asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis,irritable bowel syndrome, inflammatory bowel diseases including Crohn'sDisease or ulcerative colitis.

One embodiment of the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprising thestep of administering to a subject in need of such treatment atherapeutically effective amount of a compound, salt or solvate ofFormula (I).

A further embodiment of the present invention is directed to a methodfor treating inflammatory visceral hyperalgesia in which a enhancedvisceral irritability exists, comprising, consisting of, and/orconsisting essentially of the step of administering to a subject in needof such treatment a therapeutically effective amount of a compound, saltor solvate of Formula (I).

A further embodiment of the present invention is directed to a methodfor treating neuropathic cold allodynia in which a hypersensitivity to acooling stimuli exists, comprising, consisting of, and/or consistingessentially of the step of administering to a subject in need of suchtreatment a therapeutically effective amount of a compound, salt orsolvate of Formula (I).

Examples of an inflammatory hypersensitivity condition include urinaryincontinence, benign prostatic hypertrophy, cough, asthma, rhinitis andnasal hypersensitivity, itch, contact dermatitis and/or dermal allergy,and chronic obstructive pulmonary disease.

Examples of a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminalneuralgia, glossopharyngeal neuralgia, postherpetic neuralgia andcausalgia), lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vulvodynia,or vidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, syndrome, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below andillustrated in the schemes and examples that follow. Since the schemesare an illustration, the invention should not be construed as beinglimited by the chemical reactions and conditions described in theschemes. The various starting materials used in the schemes and examplesare commercially available or may be prepared by methods well within theskill of persons versed in the art. The variables are as defined herein.

Abbreviations used in the instant specification, particularly theschemes and examples, are as follows:

DCE 1,2-dichloroethane

DCM dichloromethane

DIAD diisopropylazodicarboxylate

DIEA or DIPEA diisopropyl-ethyl amine

DME dimethoxy ethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DPPA diphenylphosphoryl azide

ESI electron-spray ionization

Et₂O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

HEK human embryonic kidney

HPLC high performance liquid chromatography

MeCN acetonitrile

MeOH methanol

MHz megahertz

min minutes

MS mass spectroscopy

NMR nuclear magnetic resonance

RP reverse-phase

R_(t) retention time

rt room temperature

t-BuOH tert-butanol

TEA/Et₃N triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Scheme A illustrates a route for the synthesis of certain intermediatesof the present invention, wherein Y is C₁₋₆alkyl and R² is as previouslydefined.

The compounds A1 and A2 are either commercially available or may beprepared by known methods described in the scientific literature. Thecompounds A1 and A2 may be reacted in the presence of dimethoxyethane togive a compound of formula A3, which, upon heating in methanol, cyclizesto form an intermediate of formula A4.

Scheme B illustrates a route for the synthesis of certain compounds ofthe present invention, wherein Y is C₁₋₆alkyl, R¹ is an optionallysubstituted phenylmethyl, R² is as defined herein, and R³ is optionallysubstituted phenyl.

The compound of formula A4 may be treated with hydrazine in an alcoholicsolvent at elevated temperatures to afford a compound of formula B1. Thecompound of formula B1 may be treated with sodium nitrite in thepresence of a mineral acid such as hydrochloric acid, or in the presenceof an organic acid, such as trifluoroacetic acid, to afford thecorresponding acyl azide of formula B2. Upon the addition of t-butanolwith heating at elevated temperatures, the Boc-protected amine offormula B3 may be prepared. The compound of formula B3 may be treatedwith a sulfonyl chloride of formula B4 in the presence of a base such assodium hydride to afford a compound of formula B5. The compound offormula B5 may be deprotected in the presence of a mineral acid such ashydrochloric acid, or in the presence of an organic acid, such astrifluoroacetic acid, to afford a compound of formula B6 which may bealkylated with a compound of formula B7 to afford a compound of Formula(I)-B. The R^(A1) group of a compound of formula B7 is an optionalsubstituent on the phenylmethyl group of R¹ as defined in the presentinvention, and LG is an appropriate leaving group such as, but notlimited to, bromide, iodide, mesylate, triflate, and the like.

Scheme C illustrates a route for the synthesis of certain compounds ofthe present invention, wherein Y is as defined herein, R¹ is anoptionally substituted phenylmethyl, R² is as defined herein, and R³ isoptionally substituted phenyl.

The compound of formula C1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula C1 may be saponified in the presence of an alkalimetal hydroxide in refluxing methanol solvent to afford thecorresponding carboxylic acid of formula C2. Treatment of the carboxylicacid of formula C2 with t-butanol in the presence of DPPA and an organicbase such as DIPEA affords a compound of formula C3. The compound offormula C3 may be converted to a compound of Formula (I)-C using thesynthetic steps described in Scheme B for the conversion of a compoundof formula B3 to a compound of Formula (I)-B.

Scheme D illustrates a route for the synthesis of certain intermediates,wherein Y is C₃₋₆cycloalkyl, of the present invention.

A compound of formula D1 is either commercially available or may beprepared by known methods described in the scientific literature. Acompound of formula D1 may be coupled with a C₃₋₆cycloalkylboronic acidof formula D2, in the presence of a palladium catalyst, appropriateligands, and an inorganic base such as potassium phosphate and the like,to afford a compound of formula D3. The compound of formula D3 may beconverted to a compound of Formula (I) using the synthetic stepsdescribed in Scheme B for the conversion of a compound of formula B3 toa compound of Formula (I)-B.

Scheme E illustrates a route for the synthesis of certain compounds ofthe present invention, wherein R¹ is C₁₋₆alkyl substituted with onesubstituent that is C₃₋₆cycloalkyl or trifluoromethyl (substituentR^(1E)).

An alternate method for the introduction of certain R¹-substituents isan alkylation reaction, wherein a compound of formula E1 is treated withan appropriately substituted alcohol of formula E2, in an aproticsolvent such as THF, in the presence of a carbodiimide such as DIAD andthe like, and appropriate activating reagents such astriphenylphosphine, to afford a compound of Formula (I)-E.

Scheme F illustrates an alternate route for the synthesis of certaincompounds of the present invention, wherein Y is C₁₋₆alkyl, R¹ is anoptionally substituted phenylmethyl, R² is as defined herein, and R³ isoptionally substituted phenyl.

The compound of formula B3 may be deprotected by conventional methods,such as by treatment with hydrochloric acid, to afford the correspondingHCl salt, a compound of formula F1. The compound of formula F1 may bedirectly sulfonylated using a compound of formula B4 to afford acompound of formula B6. The compound of formula B6 may be converted to acompound of Formula (I)-B using the methods described in Scheme B.

SPECIFIC EXAMPLES Example 1

a) CH₂Cl₂, Br₂, 5° C.; b) 1. DME, 2-aminopyridine; 2. MeOH, reflux; c)MeOH, 3N NaOH, reflux; d) DCE, DPPA, DIPEA, t-BuOH; e) DMF, 60% NaH,4-CO₂Me-Ph-SO₂Cl; f) 4N HCl/dioxane; g) DMF, K₂CO₃, 4-OCF₃-PhCH₂Br; h)MeOH, 3N NaOH.

Step A: Ethyl 3-bromo-2-oxobutanoate (1-B)

To a solution of compound 1-A (4.8 g, 36.9 mmol) in CH₂Cl₂ (20 mL),cooled to 5° C., was added bromine (1.89 mL, 36.9 mmol), drop-wise. Thereaction mixture was allowed to warm to room temperature and stir for 18h. The reaction mixture was purged with nitrogen, diluted with EtOAc,and the organic phase washed with 10% NaHCO₃ (2×), H₂O, brine, driedover Na₂SO₄, filtered and the solvent evaporated under reduced pressureto afford compound 1-B as a yellow oil (7.50 g, 97%). ¹H-NMR (CDCl₃): δ5.15-5.20 (q, 1H), 4.32-4.45 (m, 2H), 1.82-1.85 (d, 3H), 1.38-1.41 (t,3H).

Step B: Ethyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate (1-C)

To a solution of compound 1-B (1.25 g, 5.98 mmol) in DME (5 mL) wasadded 2-aminopyridine (0.563 g, 5.98 mmol) and the reaction mixture wasallowed to warm to room temperature and stir for 18 h. The precipitatewas filtered, washed with DME and dried in vacuo to afford 1.41 g of awhite solid. The solid was dissolved in MeOH (20 mL) and refluxed for 18h. The reaction mixture was cooled and the solvent evaporated underreduced pressure. The crude residue was partitioned between EtOAc and10% NaHCO₃, the layers separated and the organic phase washed with 10%NaHCO₃, H₂O, brine, dried over Na₂SO₄, filtered and the solventevaporated under reduced pressure to afford 0.902 g of a white solid.The crude solid was purified by flash column chromatography (SiO2)eluting with a heptanes-EtOAc gradient to afford compound 1-C as a whitesolid (0.842 g, 69%). ¹H-NMR (CDCl₃): δ 7.90-7.92 (d, 1H), 7.65-7.68 (d,1H), 7.21-7.25 (q, 1H), 6.88-6.92 (t, 1H), 4.44-4.50 (q, 2H), 2.80 (s,3H), 1.44-1.48 (t, 3H); MS: m/z 205.2 (MH⁺).

Step C: 3-Methylimidazo[1,2-a]pyridine-2-carboxylic acid (1-D)

To a solution of compound 1-C (0.842 g, 4.12 mmol) in MeOH (10 mL) wasadded 3N NaOH (2.75 mL, 8.25 mmol) and the reaction mixture was refluxedfor 18 h. The reaction mixture was cooled and the solvent evaporatedunder reduced pressure. The crude residue was dissolved in H₂O andneutralized with 1N HCl to pH ˜7. The aqueous phase was evaporated todryness under reduced pressure, and the resultant white solid wassuspended in EtOH (20 mL) and stirred for 1 h. The solid was filteredand washed with EtOH. The solvent was evaporated under reduced pressureto afford compound 1-D as a white solid (0.793 g, 90%). ¹H-NMR (CD₃OD):δ 8.77-8.79 (t, 1H), 8.08-8.12 (m, 1H), 7.91-7.94 (m, 1H), 7.59-7.62 (m,1H), 2.94 (s, 3H); MS: m/z 177.1 (MH⁺).

Step D: tert-Butyl (3-methylimidazo[1,2-a]pyridin-2-yl)carbamate (1-E)

To a solution of compound 1-D (0.499 g, 2.35 mmol) in DCE (12 mL) wasadded DIPEA (0.89 mL, 5.17 mmol) followed by DPPA (0.608 mL, 2.82 mmol)and the reaction mixture was stirred at room temperature for 18 h.tert-Butanol (2.21 mL, 23.5 mmol) was added and the reaction mixture washeated at 82° C. for 4-5 h. The reaction mixture was cooled and thesolvent evaporated under reduced pressure. The crude residue waspartitioned in H₂O and EtOAc, the layers separated, and the organicphase washed with H₂O (2×), brine, dried over Na₂SO₄, filtered, and thesolvent evaporated under reduced pressure to afford 0.305 g of a beigesolid. The crude material was purified by flash column chromatography(SiO₂) eluting with 100% CH₂Cl₂ to 10% MeOH—CH₂Cl₂ gradient to affordcompound 1-E as a yellow solid (0.231 g, 40%). ¹H-NMR (CDCl₃): δ 9.8-9.9(s, 1H), 8.11-8.18 (m, 1H), 7.81-7.92 (m, 1H), 7.66-7.71 (m, 1H),7.27-7.31 (m, 1H), 2.55 (s, 3H), 1.51 (s, 9H); MS: m/z 248.3 (MH⁺).

Step E: Methyl4-(N-(tert-butyoxycarbonyl)-N-(3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(1-F)

To a solution of compound 1-E (0.174 g, 0.703 mmol) in DMF (5 mL),cooled to 0° C., was added 60% NaH (0.028 g, 0.703 mmol) and thereaction mixture was stirred at 0° C. for 20 min. Methyl4-(chlorosulfonyl)benzoate (0.247 g, 1.06 mmol) was added in one-portionand the reaction mixture was stirred at ambient temperature for 2 h. Thereaction mixture was diluted with EtOAc, washed with H₂O (2×), brine,dried over Na₂SO₄, filtered, and the solvent evaporated under reducedpressure to afford a crude solid. The crude material was purified byflash column chromatography (SiO₂) eluting with a heptanes-EtOAcgradient to afford compound 1-F as a white solid (0.188 g, 60%). ¹H-NMR(CDCl₃): δ 8.22-8.35 (dd, 2H), 7.90-7.92 (d, 1H), 7.61-7.64 (d, 1H),7.22-7.24 (m, 1H), 6.90-6.93 (m, 1H), 3.98 (s, 3H), 2.55 (s, 3H), 1.32(s, 9H); MS: m/z 446.1 (MH⁺).

Step F: Methyl4-(N-(3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate (1-G)

To compound 1-F (0.188 g, 0.422 mmol) was added 4N HCl in dioxane (6 mL)and the reaction mixture was stirred at room temperature for 18 h. Thereaction was diluted with ether, filtered, and the solid washed withether and dried in vacuo to afford compound 1-G as a white solid (0.104g, 65%). ¹H-NMR (CD₃OD): δ 8.53-8.55 (d, 1H), 8.21-8.23 (d, 2H),7.99-8.03 (m, 1H), 7.84-7.86 (d, 2H), 7.51-7.55 (m, 1H), 3.97 (s, 3H),2.07 (s, 9H); MS: m/z 346.0 (MH⁺).

Step G: Methyl4-(N-(3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate(1-H)

To a solution of compound 1-G (0.098 g, 0.284 mmol) in DMF (2.0 mL) wasadded K₂CO₃ (0.118 g, 0.851 mmol) and the reaction mixture was stirredat room temperature for 30 min. 4-Trifluoromethoxybenzyl bromide (0.80g, 0.312 mmol) was added in one-portion and the reaction mixture wasstirred at ambient temperature for 18 h. The reaction mixture wasdiluted with EtOAc, washed with H₂O (2×), brine, dried over Na₂SO₄,filtered, and the solvent evaporated under reduced pressure. The cruderesidue was purified by flash column chromatography (SiO₂) eluting witha heptanes-EtOAc gradient to afford compound 1-H as a white solid (0.090g, 61%). ¹H-NMR (CDCl₃): δ 8.15-8.18 (d, 2H), 7.86-7.88 (d, 2H),7.78-7.80 (d, 1H), 7.42-7.44 (d, 1H), 7.29-7.31 (d, 2H), 7.16-7.20 (m,1H), 7.04-7.06 (d, 1H), 6.84-6.87 (m, 1H), 4.75 (s, 2H), 3.96 (s, 3H),2.28 (s, 3H); MS: m/z 520.0 (MH⁺).

Step H: Sodium4-(N-(3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate(Compound 107)

To a solution of compound 1-H (0.101 g, 0.195 mmol) in MeOH (2 mL) wasadded 3N NaOH (0.068 μL, 0.204 mmol) and the reaction mixture was heatedat 60° C. for 18 h. The reaction mixture was cooled and the solventevaporated under reduced pressure and dried in vacuo to afford Compound107 as a white solid (0.099 g, 96%). ¹H-NMR (DMSO-d₆): δ 8.19-8.21 (d,J=8 Hz, 1H), 7.95-7.97 (d, J=8 Hz, 2H), 7.62-7.64 (d, J=8 Hz, 1H),7.46-7.48 (d, J=8 Hz, 1H), 7.36-7.38 (d, J=8 Hz, 2H), 7.23-7.25 (m, 3H),6.92-6.96 (t, 1H), 4.75 (s, 2H), 2.25 (s, 3H); MS: m/z 506.1 (MH⁺).

Example 2

-   a) DPPA, DIPEA, t-BuOH; b) DMF, 60% NaH, 4-CO₂Me-Ph-SO₂Cl; c) 4N    HCl/dioxane; d) DMF, K₂CO₃, 4-OCF₃-PhCH₂Br; e) MeOH, 1N NaOH.

Step A: tert-Butyl (3,8-dimethylimidazo[1,2-a]pyridin-2-yl)carbamate(2-B)

To a solution of compound 2-A (2.06 g, 10.8 mmol) in tert-butanol (50mL) was added DIPEA (2.05 mL, 11.9 mmol) followed by DPPA (2.80 mL, 12.9mmol), and the reaction mixture was refluxed for 18 h. The reactionmixture was cooled and the solvent evaporated under reduced pressure.The crude residue was partitioned in H₂O and EtOAc, the layersseparated, and the organic phase washed with H₂O (4×), brine, dried overNa₂SO₄, filtered, and the solvent evaporated under reduced pressure. Thecrude material was purified by flash column chromatography (SiO₂)eluting with a 0% EtOAc-heptane to 15% EtOAc-heptane to 30%EtOAc-heptane gradient to afford compound 2-B as a white solid (0.799 g,28%). ¹H-NMR (CDCl₃): δ 7.70-7.72 (d, 1H), 6.94-6.95 (m, 1H), 6.73-6.76(m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 1.50 (s, 9H); MS: m/z 262.2 (MH⁺).

Step B: Methyl4-(N-(tert-butyoxycarbonyl)-N-(3,8-dimethylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(2-C)

To a solution of compound 2-B (0.799 g, 3.06 mmol) in DMF (22 mL),cooled to 0° C., was added 60% NaH (0.147 g, 3.67 mmol) and the reactionmixture was stirred at 0° C. for 20 min. Methyl4-(chlorosulfonyl)benzoate (2.15 g, 9.17 mmol) was added in smallportions and the reaction mixture was stirred at ambient temperature for18 h. The reaction mixture was diluted with EtOAc, washed with H₂O (2×),brine, dried over Na₂SO₄, filtered, and the solvent evaporated underreduced pressure to afford a crude solid. The crude material waspurified by flash column chromatography (SiO₂) eluting with aheptanes-EtOAc gradient to afford compound 2-C as a white solid (0.693g, 49%). ¹H-NMR (CDCl₃): δ 8.38-8.40 (dd, 2H), 8.23-8.25 (dd, 2H),7.75-7.77 (d, 1H), 7.00-7.02 (d, 1H), 6.79-6.83 (m, 1H), 3.98 (s, 3H),2.51 (s, 3H), 1.59 (s, 3H), 1.34 (s, 9H); MS: m/z 460.2 (MH⁺).

Step C: Methyl4-(N-(3,8-dimethylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate (2-D)

To compound 2-C (0.693 g, 1.51 mmol) was added 4N HCl in dioxane (30 mL)and the reaction mixture was stirred at room temperature for 18 h. Thesolvent was evaporated under reduced pressure, the solid triturated withether, filtered, and the solid washed with ether and dried in vacuo toafford compound 2-D as a white solid (0.601 g, 100%). MS: m/z 360.1(MH⁺).

Step D: Methyl4-(N-(3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate(2-E).

To a solution of compound 2-D (0.126 g, 0.319 mmol) in DMF (3.0 mL) wasadded K₂CO₃ (0.088 g, 0.638 mmol) and the reaction mixture was stirredat room temperature for 30 min. 4-Trifluoromethoxybenzyl bromide (0.098g, 0.383 mmol) was added, drop-wise at 0° C. and the reaction mixturewas stirred at ambient temperature for 2 h. The reaction mixture wasdiluted with EtOAc, washed with H₂O (2×), brine, dried over Na₂SO₄,filtered, and the solvent evaporated under reduced pressure. The cruderesidue was purified by reverse-phase semi-prep HPLC, eluting with a 55%MeCN—H₂O (0.1% TFA) to 75% MeCN—H₂O (0.1% TFA) gradient. The purefractions were combined and the solvent evaporated under reducedpressure. The solid was dissolved in EtOAc, the organic phase washedwith 10% NaHCO₃, H₂O, brine, dried over Na₂SO₄, filtered, and thesolvent evaporated under reduced pressure to afford compound 2-E as awhite solid (0.107 g, 63%). ¹H-NMR (CDCl₃): δ 8.14-8.17 (d, 2H),7.94-7.96 (d, 2H), 7.62-7.64 (d, 1H), 7.30-7.32 (d, 2H), 7.05-7.07 (d,2H), 6.94-6.96 (d, 1H), 6.73-6.76 (d, 1H), 6.65 (s, 1H), 4.74 (s, 2H),3.97 (s, 3H), 2.45 (s, 3H), 2.20 (s, 3H); MS: m/z 534.2 (MH⁺).

Step E: Sodium4-(N-(3,8-dimethylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate (Compound 117)

To a solution of compound 2-E (0.107 g, 0.201 mmol) in MeOH (2 mL) wasadded 1N NaOH (0.211 μL, 0.211 mmol) and the reaction mixture was heatedat 60° C. for 18 h. The reaction mixture was cooled and the solventevaporated under reduced pressure and dried in vacuo to afford Compound117 as a white solid (0.088 g, 81%). ¹H-NMR (CD₃OD): δ 7.97-8.03 (m,2H), 6.78-6.79 (d, J=9 Hz, 1H), 7.67-7.69 (d, J=9 Hz, 2H), 7.23-7.26 (d,J=8 Hz, 2H), 6.92-7.03 (m, 3H), 6.72-6.75 (t, 1H), 4.74 (s, 2H), 2.32(s, 3H), 2.02 (s, 3H); MS: m/z 520.1 (MH⁺).

Example 3 Compound 122

The title compound was prepared according to Example 2, substitutingcompound 2-A with 7-fluoro-3-methyl-imidazo[1,2-a]pyridine-2-carboxylicacid in Step a of Example 2 and following Steps B-E in Example 2 toafford Compound 122 as an off-white solid (0.057 g). ¹H-NMR (CD₃OD): δ8.41-8.61 (m, 1H), 8.16-8.32 (m, 2H), 7.87-8.04 (m, 2H), 7.27-7.53 (d,4H), 7.10-7.26 (m, 2H), 2.20 (s, 3H); MS: m/z 524.0 (MH⁺).

Example 4

a) CH₂Cl₂, Br₂, 5° C.; b) 1. DME, 2-aminopyridine; 2. MeOH, reflux; 3.LiOH, H₂O, THF; c) 1. HCl; d) DCE, DPPA, DIPEA, t-BuOH; e) DMF, 60% NaH,4-CO₂Me-Ph-SO₂Cl; f) 4N HCl/dioxane; g) DMF, K₂CO₃, 4-OCF₃-PhCH₂Br; h)MeOH, 3N NaOH.

Step A: Methyl 2-bromo-3-methylbutanoate (4-B)

To a solution of methyl 2-oxobutanoate 4-A (4.95 g, 34.3 mmol) in CH₂Cl₂(20 mL), cooled to 5° C., was added bromine (1.76 mL, 34.3 mmol),drop-wise. The reaction mixture was allowed to warm to room temperatureand stir for 18 h. The reaction mixture was purged with nitrogen,diluted with EtOAc, and the organic phase washed with 10% NaHCO₃ (2×),H₂O, brine, dried over Na₂SO₄, filtered and the solvent evaporated underreduced pressure to afford compound 4-B as a yellow oil (6.9 g, 90%).¹H-NMR (CDCl₃): δ 4.86 (d, J=7.8 Hz, 1H), 3.93 (s, 3H), 2.32-2.42 (m,1H), 1.15 (d, J=6.6 Hz, 3H), 1.06 (d, 3H).

Step B: Lithium 3-isopropylimidazo[1,2-a]pyridine-2-carboxylate (4-C)

To a solution of compound 4-B (3.55 g, 15.4 mmol) in DME (15 mL) wasadded 2-aminopyridine (1.5 g, 15.4 mmol) and the reaction mixture wasallowed to warm to room temperature and stir for 3 days. The solvent wasevaporated in vacuo, and the residue dissolved in methanol and heated atreflux for 6 hours. The solvent was evaporated in vacuo to give thecrude product, methyl 3-isopropylimidazo[1,2-a]pyridine-2-carboxylate(85% by HPLC, 1.74 g). ¹H-NMR (CDCl₃): δ 8.18 (d, J=7.1 Hz, 1H), 7.65(d, J=9.0 Hz, 1H), 7.18-723 (m, 1H), 6.81-686 (m, 1H), 4.29-4.41 (m,1H), 3.98 (s, 3H), 1.49 (d, J=7.3 Hz, 6H) contains 30% impurity; MS: m/z219.1 (MH⁺). The crude product and lithium hydroxide monohydrate (0.294g, 7.01 mmol) in THF (25 mL) and water (1.4 mL) was heated at reflux for4 hours. The reaction mixture was cooled to rt and the crystallineprecipitate was collected by filtration, washed with THF then Et₂O, anddried in vacuo to give the product, compound 4-C, as a colorless solid(0.854 g, 26%). ¹H-NMR (CD₃OD): δ 8.39 (d, J=7.0 Hz, 1H), 7.49 (d, J=9.0Hz, 1H), 7.17-7.30 (m, 1H), 6.89 (t, J=6.8 Hz, 1H), 4.31 (spt, J=7.3 Hz,1H), 1.48 (d, J=7.3 HZ, 6H).

Step C: 3-isopropylimidazo[1,2-a]pyridine-2-carboxylic acidhydrochloride (4-D)

A solution of compound 4-C (0.764 g, 3.64 mmol) in water (7 mL) wastreated with 1N HCl (7.45 mL, 7.45 mmol), and the resultant solution wasfiltered then frozen on a dry ice/acetone bath. The water waslyophilized away to leave a mixture of compound 4-D with lithiumchloride (1.01 g, 98%) as a colorless solid, used as is in thesubsequent reaction. ¹H-NMR (CD₃OD): δ 8.84 (d, J=7.1 Hz, 1H), 7.74-7.89(m, 2H), 7.35-7.40 (m, 1H), 4.32-4.43 (m, 1H), 1.55 (d, J=7.3 Hz, 6H);MS: m/z 205.2 (MH⁺).

Step D: tert-Butyl (3-isopropylimidazo[1,2-a]pyridin-2-yl)carbamate(4-E)

To a solution of compound 4-D (1.01 g, 3.57 mmol) in DCE (20 mL) wasadded DIPEA (1.29 mL, 7.492 mmol) followed by DPPA (0.846 mL, 3.93 mmol)and the reaction mixture was stirred at room temperature for 18 hours.tert-Butanol (1.68 mL, 17.8 mmol) was added and the reaction mixture washeated at 82° C. for 10 h. The reaction mixture was cooled and thesolvent evaporated under reduced pressure. The crude residue waspartitioned in H₂O and EtOAc, the layers separated, and the organicphase washed with H₂O (2×), brine, dried over Na₂SO₄, filtered, and thesolvent evaporated under reduced pressure. The crude residue waspurified by flash column chromatography (SiO₂) eluting with a gradientof 0-10% MeOH in CH₂Cl₂ to afford compound 4-E as a yellow solid (0.267g, 27%). ¹H-NMR (CDCl₃): δ 7.99 (d, J=7.1 Hz, 1H), 7.51 (d, J=9.1 Hz,1H), 7.11-716 (m, 1H), 6.75-6.83 (m, 1H), 6.31 (br. s., 1H), 3.35 (spt,J=7.2 Hz, 1H), 1.50 (s, 9H), 1.45 (d, J=7.2 Hz, 6H); MS: m/z 276.1(MH⁺).

Step E: Methyl4-(N-(tert-butyoxycarbonyl)-N-(3-isopropylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(4-F)

To a suspension of compound 4-E (0.267 g, 0.97 mmol) in DMF (10 mL),cooled to 0° C., was added 60% NaH (0.043 g, 1.08 mmol) and the reactionmixture was stirred at 0° C. for 40 min. Methyl4-(chlorosulfonyl)benzoate (0.341 g, 1.46 mmol) was added in one-portionand the reaction mixture was stirred at ambient temperature for 2 h. Icewater was added to the reaction solution and the product was extractedinto EtOAc, washed with H₂O (2×), then brine, and dried over Na₂SO₄,filtered, and the solvent evaporated under reduced pressure to afford acrude product. The crude material was purified by flash columnchromatography (SiO₂) eluting with a gradient of EtOAc (20-60%) inheptanes to afford compound 4-F as a colorless glass (0.235 g, 51%).¹H-NMR (CDCl₃): δ 8.4 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H), 8.05(d, J=7.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.19-7.24 (m, 1H), 6.86-6.90(m, 1H), 3.98 (s, 3H), 3.37-3.50 (m, 2H), 1.50-1.59 (m, 6H under H₂Opeak), 1.32 (s, 9H); MS: m/z 474.1 (MH⁺).

Step F: Methyl4-(N-(3-isopropylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoatehydrochloride (4-G)

To a solution of compound 4-F (0.230 g, 0.486 mmol) in dioxane (3 mL)was added 4N HCl in dioxane (10 mL) and the reaction mixture was stirredat room temperature for 1 day. An additional portion of 4N HCl indioxane (5 mL) was added and the mixture stirred an additional two daysat room temperature. The solvent was evaporated in vacuo, and the solidtriturated in Et₂O, collected by filtration, washed with Et₂O and driedto afford compound 4-G as a yellow solid (0.196 g, 98%). ¹H-NMR (CD₃OD):δ 8.72 (d, J=6.8 Hz, 1H), 8.21 (d, J=8.6 Hz, 2H), 7.90-7.99 (m, 3H),7.82 (d, J=9.0 Hz, 1H), 7.45-7.50 (m, 1H), 3.94 (s, 3H), 3.12-3.23 (m,1H), 1.14 (d, J=7.1 Hz, 6H); MS: m/z 374.1 (MH⁺).

Step G: Methyl4-(N-(3-isopropylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate(Compound 108)

To a solution of compound 4-G (0.193 g, 0.517 mmol) in DMF (3.0 mL),cooled in an ice bath, was added K₂CO₃ (0.215 g, 1.56 mmol) and4-trifluoromethoxybenzyl bromide (0.091 mL g, 0.569 mmol). The resultantmixture was stirred at ambient temperature for 18 hours. The reactionmixture was partitioned between EtOAc and water. The organic layer waswashed with water (2×), brine, dried over Na₂SO₄, filtered, and thesolvent evaporated under reduced pressure. The crude residue waspurified by flash column chromatography (SiO₂) eluting with a gradientof EtOAc in heptanes to afford Compound 108 as a colorless solid (0.186g, 66%). ¹H-NMR (CDCl₃): δ 8.13-8.25 (m, 2H), 8.01 (d, J=6.8 Hz, 1H),7.89-7.97 (m, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.14-7.18 (m, 1H), 7.05 (d,J=8.3 Hz, 2H), 6.76-6.82 (m, 1H), 4.70 (br. s., 2H), 3.8 (s, 3H), 3.58(br s, 1H), 3.27-3.44 (m, 1H), 1.11 (br. s., 6H); MS: m/z 548.1 (MH⁺).

Step H: Sodium4-(N-(3-isopropylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxy)benzyl)sulfamoyl)benzoate(Compound 109)

To a solution of Compound 108 (0.180 g, 0.329 mmol) in MeOH (6 mL) wasadded 1N NaOH (0.329 mL, 0.329 mmol) and the reaction mixture was heatedat reflux for 18 hours. The reaction mixture was cooled and the solventevaporated under reduced pressure and dried in vacuo to afford Compound109 as a colorless solid (0.165 g, 90%). ¹H-NMR (DMSO-d₆): δ 8.36 (d,J=7.1 Hz, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.51 (d,J=9.0 Hz, 1H), 7.15-7.33 (m, 5H), 6.88 (t, J=6.8 Hz, 1H), 4.67 (br. s.,2H), 3.24-3.38 (m, 1H under H₂O peak), 1.06 (d, J=5.1 Hz, 6H); MS: m/z556.2 (MH⁺).

Example 5 General Synthesis of Ethylmethylimidazo[1,2-a]pyridine-2-carboxylates

a) DME; b) MeOH. Step A:2-Amino-1-(4-ethoxy-3,4-dioxobutan-2-yl)-5-fluoropyridin-1-ium bromide(5-C)

A solution 2-amino-5-fluoropyridine (5-A, 3.04 g, 27.1 mmol) and ethyl3-bromo-2-oxobutanoate (5-B, 5.67 g, 27.1 mmol) in DME (15 mL) wasstirred at rt for 1 day. The resultant solid precipitate was collectedby filtration, and washed with Et₂O, to afford compound 5-C as anoff-white solid (5.35 g, 82%), which was used without purification inthe subsequent step.

Step B: Ethyl 6-fluoro-3-methylimidazo[1,2-a]pyridine-2-carboxylate(5-D)

A solution of compound 5-C (5.35 g, 16.7 mmol) in MeOH (75 mL), washeated at reflux for 6 hours. The solution was cooled to rt, and thesolvent was evaporated in vacuo. The residue was dissolved in water andmade basic with aqueous NaHCO₃, to give a solid precipitate. The solidwas collected by filtration, dissolved into EtOAc, and dried over sodiumsulfate. The solvent was evaporated in vacuo to give compound 5-D as apale pink solid (3.4 g, 92%). ¹H-NMR (CDCl₃): δ 7.82-7.86 (m, 1H),7.64-7-68 (m, 1H), 7.15-719 (m, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.78 (s,3H), 1.46 (t, J=7.1 Hz, 3H); MS: m/z 223.0 (MH⁺).

Example 6

a) N₂H₄, EtOH; b) NaNO₂, 2N HCl; c) t-BuOH, heat; d) DMF, 60% NaH,4-CO₂Me-Ph-SO₂Cl; e) 4N HCl/dioxane; f) DMF, K₂CO₃, 4-OCF₃-PhCH₂Br; g)MeOH, 3N NaOH.

Step A: 6-Fluoro-3-methylimidazo[1,2-a]pyridine-2-carbohydrazide (6-A)

Hydrazine (4.53 mL, 144 mmol) was added to a solution of compound 5-D(2.14 g, 9.63 mmol) in EtOH (40 mL) and the resultant solution washeated at reflux for 72 h. The solvent was evaporated in vacuo, and theresidue was crystallized from iPA to afford compound 6-A as a pale pinksolid (1.83 g, 65%). ¹H-NMR (DMSO-d₆): δ 9.41 (br. s., 1H), 8.60 (dd,J=4.4, 2.1 Hz, 1H), 7.59-7.67 (m, 1H), 7.35-7.46 (m, 1H), 4.44 (br. s.,2H), 2.73 (s, 3H); MS: m/z 209.0 (MH⁺).

Step B: 6-Fluoro-3-methylimidazo[1,2-a]pyridine-2-carbonyl azide (6-B)

Compound 6-A (1.8 g, 8.65 mmol) was dissolved in 2N HCl (21.6 mL, 43.2mmol) and cooled in an ice bath. A solution of NaNO₂ (0.716 g, 10.4mmol) in water (3 mL) was added dropwise over 5 minutes and theresultant solution was stirred on the ice bath for 25 minutes, then madebasic with careful addition of a saturated aqueous solution of NaHCO₃. Asolid precipitate was collected by filtration, then dissolved in CH₂Cl₂and dried over Na₂SO₄. The solvent was evaporated in vacuo to affordcompound 6-B as a cream colored solid (1.86 g, 98%). ¹H-NMR (CDCl₃): δ7.81-7.87 (m, 1H), 7.64 (dd, J=10.0, 5.2 Hz, 1H), 7.16-7.25 (m, 1H),2.80 (s, 3H); MS: m/z 220.1 (MH⁺).

Step C: tert-Butyl(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)carbamate (6-C)

A mixture of compound 6-B (1.8 g, 8.21 mmol) in t-BuOH (25 mL) washeated at reflux for 18 hours. The solvent was evaporated in vacuo. Theresidue was pre-absorbed on silica gel, and the purified by flashchromatography using a gradient of 1M NH₃ in MeOH (2-3%) in CH₂Cl₂ toafford compound 6-C as a colorless solid (1.40 g, 64%). ¹H-NMR(DMSO-d₆): δ 9.06 (br. s., 1H), 8.43-8.50 (m, 1H), 7.46-7.54 (m, 1H),7.20-7.30 (m, 1H), 2.30 (s, 3H), 1.38-1.49 (m, 9H); MS: m/z 266.2 (MH).

Step D: Methyl4-(N-(tert-butoxycarbonyl)-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(6-D)

A solution of compound 6-C (0.70 g, 2.64 mmol) in DMF (20 mL) was cooledin an ice bath and treated with a 60% dispersion of NaH in mineral oil(0.126 g, 3.17 mmol) and stirred at ambient temp for 30 min. Thesolution was cooled on an ice bath and treated with methyl4-(chlorosulfonyl)benzoate (1.24 g, added in portions). The resultantsolution was stirred at ambient temperature for 18 hours. The solutionwas poured into ice water, and the resultant suspension was made basicwith careful addition of a saturated aqueous solution of NaHCO₃. Thesolid was collected by filtration, washed with water and air dried. Thesolid was pre-absorbed onto silica gel and purified by flashchromatography, using a gradient of EtOAc (10-60%) in heptanes as theeluant to afford compound 6-D as a colorless solid (1.1 g, 90%). MS: m/z464.1 (MH⁺).

Step E: Methyl4-(N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(6-E)

A solution of compound 6-D (1.1 g, 2.38 mmol) in 4N HCl in dioxane (15mL, 60 mmol) was stirred at rt for 18 hours. The resulting precipitatewas collected by filtration, washed with Et₂O and air dried to give thecompound 6-E, as a colorless solid (0.915 g, 96%). ¹H-NMR (DMSO-d₆): δ8.72-8.82 (m, 1H), 8.12 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H),7.66-7.76 (m, 2H), 5.77 (br. s., 2H), 3.90 (s, 3H), 2.11 (s, 3H); MS:m/z 364.0 (MH⁺).

Step F: Methyl4-(N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-(trifluoromethoxy)benzyl)sulfamoyl)benzoate(Compound 118)

A mixture of compound 6-E (0.300 g, 0.75 mmol) and K₂CO₃ (0.218 g, 1.58mmol) in DMF (5 mL) was cooled in an ice bath and treated with asolution of 4-trifluoromethoxybenzyl bromide (0.132 mL, 0.83 mmol) inDMF (1 mL) and stirred at ambient temperature for 18 hours. The solutionwas partitioned between EtOAc and water, and the organic phase wasseparated, washed with water (3×) then brine and dried over sodiumsulfate. The solvent was evaporated in vacuo, and the residue waspre-absorbed on silica gel and purified by flash chromatography, using agradient of EtOAc (10-50%) in heptanes as the eluant, to give theCompound 118, as a colorless solid (0.330 g, 82%). ¹H-NMR (CDCl₃): δ8.17 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 8H), 7.69-7.74 (m, 1H), 7.41(dd, J=9.9, 5.0 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.03-7.14 (m, 3H), 4.74(s, 2H), 3.97 (s, 3H), 2.26 (s, 3H); MS: m/z 538.0 (MH⁺).

Step G: Sodium4-(N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-(trifluoromethoxy)benzyl)sulfamoyl)benzoate(Compound 120)

A solution of Compound 118 (0.200 g, 0.372 mmol) in MeOH (10 mL) wastreated with 1N NaOH (0.383 mL, 0.383 mmol) and heated at reflux for 1day. The solvent was evaporated in vacuo to give the Compound 120, as acolorless solid (0.184 g, 91%). ¹H-NMR (DMSO-d₆): δ 8.46-8.51 (m, 1H),7.98 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.56 (dd, J=9.9, 5.3 Hz,1H), 7.21-7.41 (m, 5H), 4.75 (s, 2H), 2.25 (s, 3H); MS: m/z 524 (MH⁺ ofcarboxylic acid).

Example 7 Methyl4-(N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)sulfamoyl)benzoate(Compound 119)

The following compound was prepared according to Example 6, substituting4-trifluoromethoxybenzyl bromide with 4-fluoro-3-trifluoromethylbenzylbromide in Step F of Example 6 to afford Compound 119 as a colorlesssolid. ¹H-NMR (CDCl₃): δ 8.17 (d, J=9 Hz, 2H), 7.82 (d, J=9 Hz, 2H),7.71-7.75 (m, 1H), 7.51-7.56 (m, 1H), 7.43-7.49 (m, 1H), 7.36-7.42 (m,1H), 7.01-7.15 (m, 2H), 4.76 (s, 2H), 3.97 (s, 3H), 2.30-2.36 (m, 3H);MS: m/z 540.2 (MH⁺).

Example 8 Sodium4-(N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)benzyl)sulfamoyl)benzoate(Compound 121)

The following compound was prepared according to Example 6, substitutingcompound 119 for compound 118 in Step F of Example 6 to afford compound121 as a colorless solid. ¹H-NMR (DMSO-d₆): δ 8.47-8.54 (m, 1H), 7.99(d, J=7.8 Hz, 2H), 7.59-7.68 (m, 4H), 7.52-7.59 (m, 1H), 7.40 (t, J=9.6Hz, 1H), 7.32 (t, J=9.1 Hz, 1H), 4.81 (s, 2H), 2.28 (s, 3H); MS: m/z526.2 (MH⁺ of carboxylic acid).

Example 9

-   -   a) MeOH, H₂O, NaOH; b) DPPA, TEA, t-BuOH; c) DMF, 60% NaH,        Ph-SO₂Cl; d) TFA; e) DMF, Na₂CO₃, 3-F, 4-CF₃-PhCH₂Br.

Step A: 3-Chloro-6-trifluoromethylimidazo[1,2-a]pyridine-2-carboxylicacid (9-B)

To a solution of compound 9-A (0.820 g, 2.8 mmol) in MeOH (6 mL) wasadded NaOH (0.112 g, 2.8 mmol) in water (3 mL) and the reaction mixturewas stirred at room temperature for 5 h. The reaction mixture wasacidified with 2N hydrochloric acid to pH2 and then concentrated invacuo. Methylene chloride was added to the residue and the organic layerwas separated. Removal of the solvent under reduced pressure gavecompound 9-B (0.820 g, 87%); MS m/z (M+H⁺) 264.

Step B: tert-Butyl(3-chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)carbamate (9-C)

To a solution of compound 9-B (0.627 g, 2.37 mmol) in tert-butanol (15mL) and triethylamine (0.720 g, 7.11 mmol) was added diphenylphosphorylazide (1.30 g, 4.74 mmol) and the reaction mixture was stirred at roomtemperature for 12 h and then heated to reflux temperature for 4 h.Additional diphenylphosphoryl azide was added (0.800 g, 2.91 mmol) andthe reaction was heated to reflux temperature for 6 h. The solvent wasremoved in vacuo and methylene chloride (20 mL) was added. The organiclayer was washed with 2M sodium carbonate solution (3×10 mL) and driedover sodium sulfate. The crude material obtained after evaporation ofsolvent was purified by flash column chromatography (SiO₂) eluting witha gradient of 20-100% ethyl acetate in hexane to afford compound 9-C(0.400 g, 50%); MS m/z (M+H⁺) 336.

Step C:N-(tert-Butoxycarbonyl)-N-(3-chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(9-D)

To a solution of compound 9-C (0.100 g, 0.300 mmol) in DMF (5 mL) atroom temperature was added 60% NaH (0.012 g, 0.300 mmol) and thereaction mixture was stirred for 10 minutes. Benzenesulfonyl chloride(0.053 g, 0.300 mmol) was added and the reaction mixture was stirred atroom temperature overnight. DMF was removed in vacuo and water andmethylene chloride were added. The organic layer was washed with H₂O(2×), brine, dried over Na₂SO₄, filtered, and the solvent evaporatedunder reduced pressure to afford the crude product. The crude materialwas purified by flash column chromatography (SiO₂) eluting with agradient of 0-100% ethyl acetate in hexane to afford compound 9-D (0.040g, 28%); MS m/z (M+H⁺) 476.

Step D:N-(3-chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(9-E)

To compound 9-D (0.040 g, 0.084 mmol) was added trifluoroacetic acid (1mL) and the resulting mixture was stirred for 1 h at room temperature.The solvent was evaporated in vacuo and the crude product (0.050 g, 99%)was used in the next step without further purification; MS m/z (M+H⁺)376.

Step E:N-(3-Chloro-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)-N-(3-fluoro-4-trifluoromethylbenzyl)benzenesulfonamide(Compound 60)

To a solution of compound 9-E (0.015 g, 0.025 mmol) in DMF (2.0 mL) wasadded Na₂CO₃ (0.011 g, 0.099 mmol) and 3-fluoro-4-trifluoromethylbenzylbromide (0.006 g, 0.025 mmol). The reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated in vacuo and theresidue was purified by flash column chromatography (SiO₂) eluting witha gradient of 0-100% ethyl acetate in hexane to afford Compound 60(0.008 g, 58%); MS m/z (M+H⁺) 552.

Following the procedures described above for Example 9 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 1 MS m/z (M + H⁺) 484

Compound 2 MS m/z (M + H⁺) 448

Compound 3 MS m/z (M + H⁺) 482

Compound 4 MS m/z (M + H⁺) 464

Compound 5 MS m/z (M + H⁺) 526

Compound 7 MS m/z (M + H⁺) 516

Compound 8 ¹H NMR (CDCl₃): δ 8.05 (td, J = 0.51, 1.20 Hz, 1H), 7.79-7.86(m, 2H), 7.63- 7.68 (m, 1H), 7.51-7.58 (m, 4H), 7.41 (dd, J = 0.82, 9.60Hz, 1H), 7.22 (dd, J = 2.02, 9.60 Hz, 1H), 7.05 (t, J = 9.28 Hz, 1H),4.74 (s, 2H); MS m/z (M + H⁺) 518.

Compound 9 MS m/z (M + H⁺) 500

Compound 10 MS m/z (M + H⁺) 502

Compound 11 MS m/z (M + H⁺) 462

Compound 12 MS m/z (M + H⁺) 448

Compound 13 MS m/z (M + H⁺) 450

Compound 14 MS m/z (M + H⁺) 496

Compound 15 MS m/z (M + H⁺) 498

Compound 16 MS m/z (M + H⁺) 450

Compound 17 MS m/z (M + H⁺) 432

Compound 18 MS m/z (M + H⁺) 468

Compound 19 MS m/z (M + H⁺) 480

Compound 20 ¹H NMR (CDCl₃): δ 7.75-7.79 (m, 2H), 7.73 (ddd, J = 0.57,2.43, 3.88 Hz, 1H), 7.60-7.66 (m, 1H), 7.44-7.57 (m, 4H), 7.40 (ddd, J =0.73, 5.08, 9.85 Hz, 1H), 7.09 (ddd, J = 2.40, 7.88, 9.99 Hz, 1H),6.99-7.06 (m, 1H), 4.76 (s, 2H), 2.34 (s, 3H); MS m/z (M + H⁺) 482.

Compound 21 MS m/z (M + H⁺) 482

Compound 22 MS m/z (M + H⁺) 418

Compound 23 MS m/z (M + H⁺) 420

Compound 24 MS m/z (M + H⁺) 450

Compound 25 MS m/z (M + H⁺) 528

Compound 26 MS m/z (M + H⁺) 476

Compound 27 MS m/z (M + H⁺) 478

Compound 28 MS m/z (M + H⁺) 478

Compound 29 MS m/z (M + H⁺) 518

Compound 30 MS m/z (M + H⁺) 476

Compound 31 MS m/z (M + H⁺) 478

Compound 32 MS m/z (M + H⁺) 478

Compound 33 MS m/z (M + H⁺) 460

Compound 34 MS m/z (M + H⁺) 460

Compound 35 MS m/z (M + H⁺) 416

Compound 36 MS m/z (M + H⁺) 496

Compound 37 MS m/z (M + H⁺) 498

Compound 38 ¹H NMR (CDCl₃): δ 7.82-7.90 (m, 1H), 7.71-7.77 (m, 2H), 7.63(tt, J = 1.14, 7.45 Hz, 1H), 7.48-7.54 (m, 2H), 7.46 (t, J = 7.45 Hz,1H), 7.37 (dd, J = 0.57, 9.54 Hz, 1H), 7.18 (d, J = 9.47 Hz, 2H), 7.14(dd, J = 1.99, 9.57 Hz, 1H), 4.79 (s, 2H), 2.41 (s, 3H); MS m/z (M + H⁺)416.

Compound 39 MS m/z (M + H⁺) 476

Compound 40 MS m/z (M + H⁺) 478

Compound 41 MS m/z (M + H⁺) 478

Compound 42 MS m/z (M + H⁺) 556

Compound 43 MS m/z (M + H⁺) 480

Compound 44 MS m/z (M + H⁺) 480

Compound 45 MS m/z (M + H⁺) 496

Compound 46\ MS m/z (M + H⁺) 464

Compound 47 MS m/z (M + H⁺) 476

Compound 48 MS m/z (M + H⁺) 478

Compound 49 MS m/z (M + H⁺) 478

Compound 61 MS m/z (M + H⁺) 550

Compound 62 MS m/z (M + H⁺) 552

Compound 67 MS m/z (M + H⁺) 494

Compound 68 MS m/z (M + H⁺) 496

Compound 74 MS m/z (M + H⁺) 604

Compound 75 MS m/z (M + H⁺) 594

Compound 76 MS m/z (M + H⁺) 602

Compound 77 MS m/z (M + H⁺) 592

Compound 78 MS m/z (M + H⁺) 604

Compound 79 MS m/z (M + H⁺) 594

Compound 83 MS m/z (M + H⁺) 528

Compound 84 MS m/z (M + H⁺) 612

Compound 85 MS m/z (M + H⁺) 614

Compound 86 MS m/z (M + H⁺) 614

Example 10

-   -   a) DME rt, MeOH reflux; b) NaOH, MeOH, H₂O; c) DPPA, TEA,        t-BuOH; d) DMF, 95% NaH, Ph-SO₂Cl; e) TFA, CH₂Cl₂; f) DMF,        Na₂CO₃, 4-F, 3-CF₃-PhCH₂Br.

Step A: Methyl3-methyl-6-trifluoromethylimidazo[1,2-a]pyridine-2-carboxylate (10-C)

To a solution of compound 10-A (1.8 g, 9.23 mmol) in DME (5 mL) wasadded compound 10-B (1.5 g, 9.23 mmol) and the reaction mixture wasstirred at room temperature overnight. The solvent was removed in vacuoand the resulting residue was dissolved in methanol (9 mL) and heated toreflux temperature overnight. The solvent was removed in vacuo, thesolid obtained was basified with 1M Na₂CO₃ solution, and the aqueousmixture extracted with CH₂Cl₂ (3×). The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The resulting residue waspurified by flash column chromatography, eluting with a hexanes-EtOAcgradient to give compound 10-C as a light yellow solid (0.978 g, 41%);MS m/z (M+H⁺) 259.

Step B: 3-Methyl-6-trifluoromethylimidazo[1,2-a]pyridine-2-carboxylicacid (10-D)

To a solution of compound 10-C (0.978 g, 3.79 mmol) in MeOH (6 mL) andH₂O (3 mL) was added sodium hydroxide (0.227 g, 5.68 mmol) and thereaction mixture was stirred at room temperature overnight. The mixturewas acidified with 2N HCl to pH 4-5 and concentrated in vacuo. Theresulting residue was taken up in EtOAc, and the organic layer waswashed with H₂O and then dried over Na₂SO₄. The mixture was filtered andthe filtrate concentrated in vacuo to give compound 10-D as a lightyellow solid (0.866 g, 94%), which was used in the next reaction; MS m/z(M+H⁺) 245.

Step C: tert-Butyl(3-methyl-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)carbamate (10-E).To a solution of compound 10-D (0.860 g, 3.52 mmol) in tert-butanol (20mL) and triethylamine (1.07 g, 10.57 mmol) was added diphenylphosphorylazide (0.969 g, 3.52 mmol) and the reaction mixture was heated at refluxtemperature for 6 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 10-E as a lightyellow solid (0.447 g, 40%); MS m/z (M+H⁺) 316.

Step D:N-(tert-Butoxycarbonyl)-N-(3-methyl-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(10-F)

To a solution of compound 10-E (0.063 g, 0.2 mmol) in DMF (1 mL) at 0°C. was added 95% NaH (0.012 g, 0.5 mmol) and the reaction mixture wasstirred for 10 minutes. Benzenesulfonyl chloride (0.053 g, 0.3 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. The reaction was quenched by the addition of H₂O and thesolution was extracted with ethyl acetate. After separation of theorganic and aqueous layers a sufficient amount of water was added toremove any dissolved DMF from the organic layer. The organic layer wasdried over Na₂SO₄, filtered, and the solvent evaporated under reducedpressure to afford the crude product. The crude material was purified byflash column chromatography, eluting with a hexanes-EtOAc gradient togive compound 10-F as a white solid (0.066 g, 72%); MS m/z (M+H⁺) 456.

Step E:N-(3-Methyl-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(10-G)

To a solution of compound 10-F (0.066 g, 0.084 mmol) in methylenechloride (2 mL) was added trifluoroacetic acid (1 mL) and the resultingmixture was stirred at room temperature overnight. The solvent wasevaporated in vacuo and the crude product, isolated as a light yellowoil, was used in the next step without further purification; MS m/z(M+H⁺) 356.

Step F:N-(3-Fluoro-4-trifluoromethylbenzyl)-N-(3-methyl-6-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(Compound 100)

To a solution of compound 10-G (0.023 g, 0.048 mmol) in DMF (1 mL) wasadded Na₂CO₃ (0.015 g, 0.14 mmol) and 3-fluoro-4-trifluoromethylbenzylbromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated in vacuo and the residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound100 as a yellow solid (0.017 g, 66%); MS m/z (M+H⁺) 532.

Following the procedures described above for Example 10 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 50 MS m/z (M + H⁺) 492

Compound 51 MS m/z (M + H⁺) 492

Compound 52 MS m/z (M + H⁺) 490

Compound 53 MS m/z (M + H⁺) 474

Compound 54 MS m/z (M + H⁺) 474

Compound 82 MS m/z (M + H⁺) 512

Compound 87 MS m/z (M + H⁺) 598

Compound 88 MS m/z (M + H⁺) 578

Compound 89 MS m/z (M + H⁺) 576

Compound 101 MS m/z (M + H⁺) 532

Example 11

-   -   a) DPPA, TEA, t-BuOH; b) DMF, 95% NaH

11-C; c) TFA, CH₂Cl₂; d) DMF, Na₂CO₃, 4-F, 3-CF₃-PhCH₂Br. Step A:tert-Butyl (3-chloroimidazo[1,2-a]pyridin-2-yl)carbamate (11-B)

To a solution of compound 11-A (0.393 g, 2.0 mmol) in tert-butanol (8mL) and triethylamine (0.61 g, 6.0 mmol) was added diphenylphosphorylazide (0.550 g, 2.0 mmol) and the reaction mixture was heated at refluxtemperature for 6 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 11-B as a lightyellow solid (0.337 g, 63%); MS m/z (M+H⁺) 268.

Step B:N-(tert-Butoxycarbonyl)-N-(3-chloroimidazo[1,2-a]pyridin-2-yl)-6-morpholin-4-yl-pyridine-3-sulfonamide(11-C)

To a solution of compound 11-B (0.080 g, 0.3 mmol) in DMF (2 mL) at 0°C. was added 95% NaH (0.019 g, 0.75 mmol) and the reaction mixture wasstirred for 10 minutes. Compound 11-C (0.118 g, 0.45 mmol) was added andthe reaction mixture was stirred at room temperature overnight. Thereaction was quenched by the addition of H₂O and the solution wasextracted with ethyl acetate. After separation of the organic andaqueous layers a sufficient amount of water was added to remove anydissolved DMF from the organic layer. The organic layer was dried overNa₂SO₄, filtered, and the solvent evaporated under reduced pressure toafford the crude product. The crude material was purified by flashcolumn chromatography, eluting with a hexanes-EtOAc gradient to givecompound 11-D as a white solid (0.130 g, 88%); MS m/z (M+H⁺) 494.

Step C:N-(3-Chloroimidazo[1,2-a]pyridin-2-yl)-6-morpholin-4-yl-pyridine-3-sulfonamide(11-E)

To a solution of compound 11-D (0.120 g, 0.24 mmol) in methylenechloride (4 mL) was added trifluoroacetic acid (2 mL) and the resultingmixture was stirred at room temperature overnight. The solvent wasevaporated in vacuo and the crude product, isolated as a light yellowoil, was used in the next step without further purification; MS m/z(M+H⁺) 394.

Step D:N-(3-Chloroimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-trifluoromethylbenzyl)-6-morpholin-4-yl-pyridine-3-sulfonamide(Compound 90)

To a solution of compound 11-E (0.030 g, 0.049 mmol) in DMF (1 mL) wasadded Na₂CO₃ (0.015 g, 0.15 mmol) and 4-fluoro-3-trifluoromethylbenzylbromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated in vacuo and the residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound90 as a yellow solid (0.008 g, 29%); MS m/z (M+H⁺) 570.

Following the procedures described above for Example 11 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 80 MS m/z (M + H⁺) 492

Compound 91 MS m/z (M + H⁺) 570

Compound 92 MS m/z (M + H⁺) 568

Compound 93 MS m/z (M + H⁺) 552

Compound 94 MS m/z (M + H⁺) 552

Compound 95 MS m/z (M + H⁺) 550

Compound 96 MS m/z (M + H⁺) 550

Compound 97 MS m/z (M + H⁺) 548

Compound 98 MS m/z (M + H⁺) 532

Compound 99 MS m/z (M + H⁺) 532

Example 12

-   -   a) Cyclopropylboronic acid, Pd(OAc)₂, P(Cy)₃, K₃PO₄,        toluene/H₂O, 100° C.; b) NaOH, MeOH, H₂O; c) DPPA, TEA,        t-BuOH; d) DMF, 95% NaH, Ph-SO₂Cl; e) TFA, CH₂Cl₂; f) DMF,        Na₂CO₃, 4-F, 3-CF₃-PhCH₂Br.

Step A: Ethyl 3-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (12-B)

Cyclopropylboronic acid (711 mg, 8.3 mmol) was added to a toluene (27mL)/water (1.4 mL) solution of Compound 12-A (1.60 g, 5.9 mmol),Pd(OAc)₂ (67 mg, 0.3 mmol), P(Cy)₃ (167 mg, 0.6 mmol), and K₃PO₄ (4.5 g,20.8 mmol). The resulting mixture was heated to 100° C. After 5 h themixture was cooled, filtered and extracted with EtOAc. The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄),concentrated and purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give Compound 12-B (1.04 g, 87%); MS m/z(M+H⁺) 231.

Step B: 3-Cyclopropylimidazo[1,2-a]pyridine-2-carboxylic acid (12-C)

To a solution of compound 12-B (1.04 g, 4.52 mmol) in MeOH (6 mL) andH₂O (3 mL) was added sodium hydroxide (0.241 g, 6.04 mmol) and thereaction mixture was stirred at room temperature overnight. The mixturewas acidified with 2N HCl to pH 4-5 and concentrated in vacuo. Theresulting residue was taken up in EtOAc, and the organic layer waswashed with H₂O and then dried over Na₂SO₄. The mixture was filtered andthe filtrate concentrated in vacuo to give Compound 12-C (0.841 g, 92%),which was used as such in the next reaction; MS m/z (M+H⁺) 203.

Step C: tert-Butyl (3-cyclopropylimidazo[1,2-a]pyridin-2-yl)carbamate(12-D)

To a solution of compound 12-C (0.841 g, 4.16 mmol) in tert-butanol (17mL) and triethylamine (1.27 g, 12.48 mmol) was added diphenylphosphorylazide (1.14 g, 4.16 mmol) and the reaction mixture was heated at refluxtemperature for 7 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 12-D (0.171 g,15%); MS m/z (M+H⁺) 274.

Step D:N-(tert-Butoxycarbonyl)-N-(3-cyclopropylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(12-E)

To a solution of compound 12-D (0.171 g, 0.63 mmol) in DMF (3.5 mL) atroom temperature was added 95% NaH (0.040 g, 1.56 mmol) and the reactionmixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.166 g,0.94 mmol) dissolved in DMF (1 mL) was added and the reaction mixturewas stirred at room temperature overnight. The reaction was quenched bythe addition of H₂O and the solution was extracted with ethyl acetate.After separation of the organic and aqueous layers a sufficient amountof water was added to remove any dissolved DMF from the organic layer.The organic layer was dried over Na₂SO₄, filtered, and the solventevaporated under reduced pressure to afford the crude product. The crudematerial was purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give compound 12-E as a white solid (0.148 g,57%); MS m/z (M+H⁺) 414.

Step E: N-(3-Cyclopropylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(12-F)

To a solution of compound 12-E (0.083 g, 0.2 mmol) in methylene chloride(2 mL) was added trifluoroacetic acid (1 mL) and the resulting mixturewas stirred at room temperature for 5 h. The solvent was evaporated invacuo and the crude product, isolated as a light yellow oil, was used inthe next step without further purification; MS m/z (M+H⁺) 314.

Step F:N-(3-Chloroimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-trifluoromethylbenzyl)benzenesulfonamide(Compound 69)

To a solution of compound 12-F (0.022 g, 0.04 mmol) in DMF (1 mL) wasadded Na₂CO₃ (0.013 g, 0.12 mmol) and 4-fluoro-3-trifluoromethylbenzylbromide (0.011 g, 0.04 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated in vacuo and the residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound69 as a white solid (0.007 g, 36%); MS m/z (M+H⁺) 490.

Following the procedures described above for Example 12 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 70 MS m/z (M + H⁺) 490

Compound 71 MS m/z (M + H⁺) 488

Compound 72 MS m/z (M + H⁺) 472

Compound 73 MS m/z (M + H⁺) 472

Example 13

-   -   a) NaOH, MeOH, H₂O; b) DPPA, TEA, t-BuOH; c) DMF, 95% NaH,        Ph-SO₂Cl; d) TFA, CH₂Cl₂; e) DMF, Na₂CO₃, 4-F, 3-CF₃-PhCH₂Br.        Step A:        3-Ethyl-8-trifluoromethylimidazo[1,2-a]pyridine-2-carboxylate        (13-B). To a solution of compound 13-A (0.696 g, 2.56 mmol) in        MeOH (3.4 mL) and H₂O (1.7 mL) was added sodium hydroxide (0.136        g, 3.42 mmol) and the reaction mixture was stirred at room        temperature overnight. The mixture was acidified with 2N HCl to        pH 4-5 and concentrated in vacuo. The resulting residue was        taken up in EtOAc, and the organic layer was washed with H₂O and        then dried over Na₂SO₄. The mixture was filtered and the        filtrate concentrated in vacuo to give compound 13-B (0.620 g,        94%), which was used as such in the next reaction; MS m/z (M+H⁺)        259.

Step B: tert-Butyl(3-ethyl-8-trifluoromethylimidazo[1,2-a]pyridin-2-yl)carbamate (13-C)

To a solution of compound 13-B (0.620 g, 2.40 mmol) in tert-butanol (10mL) and triethylamine (0.733 g, 7.2 mmol) was added diphenylphosphorylazide (0.658 g, 2.4 mmol) and the reaction mixture was heated at refluxtemperature for 7 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 13-C (0.450 g,57%); MS m/z (M+H⁺) 330.

Step C:N-(tert-Butoxycarbonyl)-N-(3-ethyl-8-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(13-D)

To a solution of compound 13-C (0.450 g, 1.37 mmol) in DMF (7.5 mL) atroom temperature was added 95% NaH (0.086 g, 3.42 mmol) and the reactionmixture was stirred for 10 minutes. Benzenesulfonyl chloride (0.362 g,2.05 mmol) dissolved in DMF (2.5 mL) was added and the reaction mixturewas stirred at room temperature overnight. The reaction was quenched bythe addition of H₂O and the solution was extracted with ethyl acetate.After separation of the organic and aqueous layers a sufficient amountof water was added to remove any dissolved DMF from the organic layer.The organic layer was dried over Na₂SO₄, filtered, and the solventevaporated under reduced pressure to afford the crude product. The crudematerial was purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give compound 13-D (0.552 g, 86%); MS m/z(M+H⁺) 470.

Step D:N-(3-Ethyl-8-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(13-E)

To a solution of compound 13-D (0.235 g, 0.5 mmol) in methylene chloride(4 mL) was added trifluoroacetic acid (2 mL) and the resulting mixturewas stirred at room temperature for 5 h. The solvent was evaporated invacuo and the crude product, isolated as a light yellow oil, was used inthe next step without further purification; MS m/z (M+H⁺) 370.

Step E:N-(3-Ethyl-8-trifluoromethylimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-trifluoromethylbenzyl)benzenesulfonamide(Compound 55)

To a solution of compound 13-E (0.060 g, 0.1 mmol) in DMF (3 mL) wasadded Na₂CO₃ (0.032 g, 0.3 mmol) and 4-fluoro-3-trifluoromethylbenzylbromide (0.028 g, 0.11 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated in vacuo and the residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound55 as a white solid (0.047 g, 87%); MS m/z (M+H⁺) 546.

Following the procedures described above for Example 13 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 56 MS m/z (M + H⁺) 546

Compound 57 MS m/z (M + H⁺) 544

Compound 58 MS m/z (M + H⁺) 528

Compound 59 MS m/z (M + H⁺) 528

Example 14

-   -   a) DIAD, PPh₃, THF.

N-(2-Cyclopropylethyl)-N-(3-ethyl-8-trifluoromethylimidazo[1,2-a]pyridin-2-yl)benzenesulfonamide(Compound 63)

To a solution of compound 13-E (0.074 g, 0.2 mmol), compound 14-A (0.021g, 0.24 mmol), and triphenylphosphine (0.068 g, 0.26 mmol) in THF (2 mL)was added diisopropylazodicarboxylate (0.053 g, 0.26 mmol) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was diluted with water and ethyl acetate. The organic layer wasseparated, washed with saturated aqueous sodium bicarbonate (2×), anddried over sodium sulfate. The solvent was evaporated in vacuo and theresidue was purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give Compound 63 as a white solid (0.036 g,41%); MS m/z (M+H⁺) 438.

Following the procedures described above for Example 14 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 64 MS m/z (M + H⁺) 494

Compound 65 MS m/z (M + H⁺) 424

Compound 66 MS m/z (M + H⁺) 466

Example 15

-   -   a) DPPA, TEA, t-BuOH; b) DMF, 60% NaH, methyl        4-chlorosulfonylbenzoate; c) HCl, dioxane; d) DMF, Na₂CO₃,        4-OCF₃-PhCH₂Br; e) NaOH, H₂O, MeOH.

Step A: tert-Butyl(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)carbamate (15-B)

To a solution of compound 15-A (1.26 g, 6.0 mmol) in tert-butanol (24mL) and triethylamine (1.83 g, 18 mmol) was added diphenylphosphorylazide (1.65 g, 6.0 mmol) and the reaction mixture was heated at refluxtemperature for 6 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 15-B as a lightyellow solid (0.975 g, 58%); MS m/z (M+H⁺) 282.

Step B: Methyl4-(N-(tert-Butoxycarbonyl)-N-(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoate(15-C)

To a solution of compound 15-B (0.563 g, 2.0 mmol) in DMF (13 mL) at 0°C. was added 60% NaH (0.096 g, 2.4 mmol) and the reaction mixture wasstirred for 10 minutes. Benzenesulfonyl chloride (0.563 g, 2.4 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. The reaction was quenched by the addition of H₂O and thesolution was extracted with ethyl acetate. After separation of theorganic and aqueous layers a sufficient amount of water was added toremove any dissolved DMF from the organic layer. The organic layer wasdried over Na₂SO₄, filtered, and the solvent evaporated under reducedpressure to afford the crude product. The crude material was purified byflash column chromatography, eluting with a hexanes-EtOAc gradient togive compound 15-C as a white solid (0.825 g, 86%); MS m/z (M+H⁺) 480.

Step C: Methyl4-(N-(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoyl)benzoatehydrochloride (15-D)

Compound 15-C (0.820 g, 1.71 mmol) was dissolved in 4N HCl in dioxane(44 mL) and the reaction mixture was stirred for 24 h at roomtemperature. The solvent was evaporated in vacuo and the crude productwas washed with ethyl ether. The resulting solid was filtered, washedwith additional ethyl ether, and dried in vacuo to give compound 15-D asa white solid (0.610 g, 86%); MS m/z (M+H⁺) 380.

Step D: Methyl4-(N-(6-Chloro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxybenzyl)sulfamoyl)benzoate(Compound 110)

To a solution of compound 15-D (0.083 g, 0.2 mmol) in DMF (2 mL) wasadded Na₂CO₃ (0.064 g, 0.6 mmol) and 4-trifluoromethoxybenzyl bromide(0.056 g, 0.02 mmol) at 0° C. The reaction mixture was allowed to warmto room temperature and stirred for 5 h. The reaction mixture wasdiluted with ethyl acetate, washed with water, and dried over sodiumsulfate. The solvent was evaporated in vacuo and the residue waspurified by flash column chromatography, eluting with a hexanes-EtOAcgradient to give Compound 110 as a white solid (0.078 g, 70%); MS m/z(M+H⁺) 554.

Step E: Sodium4-(N-(6-Chloro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-trifluoromethoxybenzyl)sulfamoyl)benzoate(Compound 113)

To a solution of Compound 110 (0.067 g, 0.12 mmol) in methanol (1.2 mL)was added 3N NaOH (42.33 μL, 0.13 mmol) and the reaction mixture washeated at 60° C. for 13 h. The reaction mixture was cooled to roomtemperature, the solvent evaporated under reduced pressure to giveCompound 113 as a white solid (0.068 g, 99%); ¹H NMR (MeOD): δ 8.21-8.31(m, 1H), 8.05-8.14 (m, J=8.31 Hz, 2H), 7.68-7.78 (m, J=8.31 Hz, 2H),7.36-7.40 (m, J=9.54 Hz, 1H), 7.34 (d, J=8.56 Hz, 2H), 7.28 (dd, J=1.71,9.54 Hz, 1H), 7.12 (d, J=8.07 Hz, 2H), 4.81 (s, 2H), 2.23 (s, 3H); MSm/z (M+H⁺) 540.

Following the procedures described above for Example 15 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 6 ¹H NMR (MeOD): δ 8.19 (d, J = 7.09 Hz, 1H), 8.09-8.15 (m, J =8.31 Hz, 2H), 7.79-7.85 (m, J = 8.56 Hz, 2H), 7.47 (d, J = 9.54 Hz, 1H),7.33-7.42 (m, 3H), 7.04-7.15 (m, 3H), 4.81 (s, 2H); MS m/z (M + H⁺) 526.

Compound 111 MS m/z (M + H⁺) 506

Compound 112 MS m/z (M + H⁺) 556

Compound 114 ¹H NMR (MeOD): δ 8.29 (s, 1H), 8.02- 8.14 (m, J = 8.31 Hz,2H), 7.69-7.78 (m, J = 8.31 Hz, 2H), 7.38 (d, J = 9.54 Hz, 1H), 7.28(dd, J = 1.83, 9.66 Hz, 1H), 7.16-7.26 (m, 1H), 7.05-7.15 (m, 1H),6.98-7.05 (m, 1H), 4.76 (s, 2H), 2.28 (s, 3H); MS m/z (M + H⁺) 492.

Compound 115 ¹H NMR (MeOD): δ 8.29 (s, 1H), 8.05- 8.13 (m, J = 8.31 Hz,2H), 7.69-7.78 (m, J = 8.31 Hz, 2H), 7.60 (d, J = 6.60 Hz, 1H),7.49-7.57 (m, 1H), 7.38 (d, J = 9.78 Hz, 1H), 7.29 (dd, J = 1.83, 9.66Hz, 1H), 7.11-7.23 (m, 1H), 4.84 (s, 2H), 2.27 (s, 3H); MS m/z (M + H⁺)542.

Compound 116 MS m/z (M + H⁺) 540

Example 16

-   -   a) HCl, dioxane, MeOH; b)

16-B, pyridine; c) DMF, Na₂CO₃, 4-F, 3-CF₃-PhCH₂Br.

Step A: 2-Amino-6-chloro-3-methylimidazo[1,2-a]pyridine hydrochloride(16-A)

Compound 15-B (0.500 g, 1.77 mmol) was dissolved in 4N HCl in dioxane(17.75 mL) and methanol (12 mL) and the reaction mixture was stirred for3 h at room temperature. The solvent was evaporated in vacuo to givecompound 16-A as a light yellow solid; MS m/z (M+H⁺) 182.

Step B:N-(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)-4-(1H-pyrazol-1-yl)benzenesulfonamide(16-C)

To a solution of compound 16-A (0.065 g, 0.3 mmol) in pyridine (1.5 mL)at 0° C. was added compound 16-B (0.087 g, 0.36 mmol). The ice bath wasremoved and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo, and the crudeproduct was purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give compound 16-C (0.045 g, 39%) as a lightyellow solid; MS m/z (M+H⁺) 388.

Step C:N-(6-chloro-3-methylimidazo[1,2-a]pyridin-2-yl)-N-(4-fluoro-3-trifluoromethylbenzyl)-4-(1H-pyrazol-1-yl)benzenesulfonamide(Compound 102)

To a solution of compound 16-C (0.011 g, 0.27 mmol) in DMF (0.5 mL) wasadded Na₂CO₃ (0.0057 g, 0.054 mmol) and 4-fluoro-3-trifluoromethylbenzylbromide (0.0077 g, 0.03 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate, washed with water, and dried over sodium sulfate. The solventwas evaporated in vacuo and the residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound102 (0.011 g, 72%) as a white solid; MS m/z (M+H⁺) 564.

Following the procedures described above for Example 16 and substitutingthe appropriate reagents, starting materials and purification methodsknown to those skilled in the art, the following compounds of thepresent invention were prepared:

Compound Spectral Data

Compound 103 MS m/z (M + H⁺) 564

Compound 104 MS m/z (M + H⁺) 562

Compound 105 MS m/z (M + H⁺) 546

Example 17

-   -   a) NaOH, MeOH, H₂O; b) DPPA, TEA, t-BuOH; c) HCl, dioxane; d)        MeO₂CCH₂SO₂Cl, pyridine, CH₂Cl₂; e) DIAD, PPh₃,        4-trifluoromethoxybenzyl alcohol, THF; f) LAH, THF; g) CBr₄,        PPh₃, CH₂Cl₂; h) diisobutylamine, CH₃CN.

Step A: 7-Trifluoromethyl-3-methylimidazo[1,2-a]pyridine-2-carboxylate(17-B)

To a solution of compound 17-A (0.978 g, 3.79 mmol) in MeOH (6 mL) andH₂O (3 mL) was added sodium hydroxide (0.227 g, 5.68 mmol) and thereaction mixture was stirred at room temperature overnight. The mixturewas acidified with 2N HCl to pH 4-5 and concentrated in vacuo. Theresulting residue was taken up in EtOAc, and the organic layer waswashed with H₂O and then dried over Na₂SO₄. The mixture was filtered andthe filtrate concentrated in vacuo to give compound 17-B as a lightyellow solid (0.866 g, 94%), which was used as such in the nextreaction; MS m/z (M+H⁺) 245.

Step B: tert-Butyl(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)carbamate (17-C)

To a solution of compound 17-B (0.860 g, 3.52 mmol) in tert-butanol (20mL) and triethylamine (1.07 g, 10.57 mmol) was added diphenylphosphorylazide (0.969 g, 3.52 mmol) and the reaction mixture was heated at refluxtemperature for 6 h. The solvent was removed in vacuo and ethyl acetatewas added. The organic layer was washed with 1M sodium carbonatesolution, dried over sodium sulfate, and the solvent removed in vacuo.The resulting residue was purified by flash column chromatography,eluting with a hexanes-EtOAc gradient to give compound 17-C as a lightyellow solid (0.447 g, 40%); MS m/z (M+H⁺) 316.

Step C: 2-Amino-7-trifluoromethyl-3-methylimidazo[1,2-a]pyridinehydrochloride (17-D)

Compound 17-C (0.221 g, 0.7 mmol) was dissolved in 4N HCl in dioxane (7mL) and the reaction mixture was stirred for 2 h at room temperature.The solvent was evaporated in vacuo to give compound 17-D as a lightyellow solid; MS m/z (M+H⁺) 216.

Step D: MethylN-(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoylacetate(17-E)

To a solution of compound 17-D (0.176 g, 0.7 mmol) and pyridine (0.116g, 1.47 mmol) in methylene chloride (2 mL) at 0° C. was added methylchlorosulfonylacetate (0.127 g, 0.74 mmol) in methylene chloride (1 mL).The reaction mixture was allowed to warm slowly to room temperature andstirred overnight. Additional methyl chlorosulfonylacetate (0.036 g) inmethylene chloride (0.3 mL) and pyridine (0.035 g) were added at 0° C.and the reaction mixture was allowed to warm slowly to room temperatureand stirred overnight. An additional amount of methylchlorosulfonylacetate (0.036 g) in methylene chloride (0.3 mL) andpyridine (0.035 g) were added at 0° C. and the reaction mixture wasallowed to warm slowly to room temperature and stirred for an additional3 h. The reaction mixture was concentrated in vacuo. The crude productwas purified by flash column chromatography, eluting with ahexanes-EtOAc gradient to give compound 17-E as a light yellow solid(0.160 g, 65%); MS m/z (M+H⁺) 352.

Step E: MethylN-(4-trifluoromethoxybenzyl)-N-(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)sulfamoylacetate(17-F)

To a solution of compound 17-E (0.155 g, 0.44 mmol),4-trifluoromethoxybenzyl alcohol (0.110 g, 0.57 mmol), andtriphenylphosphine (0.150 g, 0.57 mmol) in THF (4.5 mL) was addeddiisopropylazodicarboxylate (0.116 g, 0.57 mmol) and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas concentrated in vacuo and the resulting residue was purified byflash column chromatography, eluting with a hexanes-EtOAc gradient togive compound 17-F as a light yellow gum (0.231 g, 100%); MS m/z (M+H⁺)526.

Step F:N-(4-Trifluoromethoxybenzyl)-N-(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)-2-hydroxyethylsulfonamide(17-G)

To a solution of compound 17-F (0.226 g, 0.43 mmol) in THF (8 mL) at 0°C. was added lithium aluminum hydride (1M in THF, 0.43 mL, 0.43 mmol)and the reaction mixture was stirred for 1 h at 0° C. To the stirredmixture at 0° C. was added water and the resulting mixture wasconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography, eluting with a hexanes-EtOAc gradient to givecompound 17-G as a colorless gum (0.031 g, 14%); MS m/z (M+H⁺) 498.

Step G:N-(4-Trifluoromethoxybenzyl)-N-(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)-2-bromoethylsulfonamide(17-H)

To a solution of compound 17-G (0.031 g, 0.062 mmol) and carbontetrabromide (0.025 g, 0.075 mmol) in methylene chloride (1.5 mL) at 0°C. was added triphenylphosphine (0.020 g, 0.075 mmol). The ice bath wasremoved and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo and theresulting residue was purified by flash column chromatography, elutingwith a hexanes-EtOAc gradient to give compound 17-H as a white solid(0.010 g, 29%); MS m/z (M+H⁺) 560.

Step H:N-(4-Trifluoromethoxybenzyl)-N-(7-trifluoromethyl-3-methylimidazo[1,2-a]pyridin-2-yl)-2-(N,N-diisobutylamino)ethylsulfonamide(Compound 106)

To a solution of compound 17-H (0.004 g, 0.007 mmol) in acetonitrile(0.4 mL) was added diisobutylamine (0.009 g, 0.071 mmol) and thereaction mixture was heated at 80° C. for 18 h. The solvent was removedin vacuo and the resulting residue was purified by flash columnchromatography, eluting with a hexanes-EtOAc gradient to give Compound106 as a white solid (0.004 g, 97%); MS m/z (M+H⁺) 609.

BIOLOGICAL EXAMPLES Example 1 In Vitro Canine TRPM8 Functional Assay

The functional activity of compounds of the formula (I) was determinedby measuring changes in intracellular calcium concentration using aCa²⁺-sensitive fluorescent dye. The changes in fluorescent signal weremonitored by a fluorescence plate reader, either a FLIPR™ (MolecularDevices) or FDSS (Hamamatsu). Increases in intracellular Ca²⁺concentration were readily detected upon activation with icilin.

At 24 hrs prior to assay, HEK293 cells stably expressing canine TRPM8were seeded in culture medium in black wall, clear-base poly-D-lysinecoated 384-well plates (BD Biosciences, NJ, USA) and grown overnight in5% CO₂ at 37° C. On assay day, growth media was removed and cells wereloaded with Calcium 3 Dye (Molecular Devices) for 35 min at 37° C.,under 5% CO₂ and then for 25 min at room temperature and atmosphere.Subsequently, cells were tested for agonist-induced increases inintracellular Ca²⁺ levels using FLIPR™ or FDSS. Cells were challengedwith a compound of the Formula (I) (at varying concentrations) andintracellular Ca²⁺ was measured for 5 min prior to the addition oficilin to all wells to achieve a final concentration that producesapproximately an 80% maximal response. EC₅₀ or IC₅₀ values for compoundsof the present invention were determined from eight-point dose-responsestudies. Curves were generated using the average of quadruplicate wellsfor each data point. The resultant data are displayed in Tables 1 and 2.

TABLE 1 Cpd % Inh (%) No TRPM8 IC50 (μM) @ 0.2 μM 1 0.00325 3 0.00180 40.0167 5 0.00530 6  0.0302, 0.00224 102 7 0.0298 8 0.0183, 0.0235,0.0286 97, 96 9 0.0136 10 0.0174 11 0.00568 12 0.0487 13 0.0489 140.0207 15 0.0160 16 0.0720 17 0.0743 18 0.0786 19 0.0144 20 0.0101 210.0106, 0.0124 22 51 23 58 24 0.01337 25 0.00349 26 0.0101 100 270.00611 100 28 0.00801 100 29 0.0322 90 30 0.0100 100 31 0.0103 101 320.0125 100 33 0.0267 99 34 0.00983 100 35 0.0449 74 36 0.0225 100 370.0294 100 38 0.00876, 0.0194  100 39 0.0289 99 40 0.0222 100 41 0.0253100 42 0.0254 99 43 0.0243 99 44 0.0183 100 45 0.0390 99 46 0.0136 99 470.0104 100 48 0.0110 99 49 0.0133 99 50 0.0123 101 51 0.00656 101 520.00943 101 53 0.00319 101 54 0.00792 101 55 0.0334 94 56 0.0650 99 570.0966 82 58 0.0715 87 59 0.0802 97 60 55 61 47 62 56 63 0.0241 99 640.0220 99 65 0.0628 72 66 0.0774 83 67 0.0621 96 68 0.04164 100 690.0282 101 70 0.00821 101 71 0.0215 101 72 0.0113 101 73 0.0372 100 740.0626 74 75 0.00194 99 76 0.0705 72 77 0.00227 100 78 26 79 0.00317 9980 0.0121 99 81 0.0197 99 82 0.0142 100 83 0.0746 87 84 0.0115 100 850.0312 100 86 0.0107 99 87 0.0863 86 88 0.0414 100 89 0.0250 99 900.0269 99 91 0.0416 99 92 0.0250 99 93 0.0269 98 94 0.0484 97 95 0.0070099 96 0.00550 100 97 0.00848 99 98 0.00404 99 99 0.0151 99 100 31 101 22102 0.02183 100 103 0.0245 98 104 0.0516 93 105 0.0303 98 107 0.00568101 108 0.0104 101 109 0.00231 101 110 0.0572 82 111 0.0815 73 1120.0821 83 113 0.0146 102 114 38 115 0.0349 96 116 0.00529 102 117 0.0135101 118 0.0180 100 119 0.0239 100 120 0.0122 102 121 0.0328 101 1220.00403 99

TABLE 2 EC50 Cpd No (μM) % Eff (%) @0.24 μM 106 0.093 111

In Vivo Models Example 2 Inhibition of Icilin-Induced Behaviors inRodents

Icilin was initially developed as a “super-cooling” compound by DelmarChemicals Ltd. Subsequently it was shown to be one of the most potentknown agonists of TRPM8 (McKemy D D, et al. Nature 2002, 416(6876):52-8), having an EC₅₀=0.2 μM in stimulating calcium ion influx intoTRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004,141(4): 737-45). Initial in vivo testing of icilin showed it to cause“wet-dog” shakes in rats. Similar shaking or jumping behavior was alsoevident in mice, rabbits, cats, dogs and monkeys. In humans, icilinproduced a sensation of coolness on contact with mucous membranes, coldprickling when 0.1 mg was dropped on the tongue and coldness in themouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingestedorally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). Theinhibition or reversal of icilin-induced shaking behaviors in rodentsprovides evidence for the utility of TRPM8 antagonists of the formula(I) in treating or preventing a disease, syndrome, disorder, orcondition in a subject in which the disease, syndrome, disorder orcondition is affected by the modulation of TRPM8 receptors.

Example 2a Inhibition of Icilin-Induced “Wet-Dog” Shakes in Rats

Male Sprague Dawley rats (220-450 g, Charles River Labs,n=6-9/treatment) may be used to evaluate the ability of selectedcompounds of the formula (I) to block icilin-induced “wet-dog” shakes(WDS). Compounds of the formula (I) may be administered in anappropriate vehicle, such as hydroxypropyl-β-cyclodextrin (HPIβCD),methocellulose, 10% Solutol, or H₂O, or the like, by the appropriateroute, i.p. or p.o., 30-120 minutes before icilin. Icilin may beadministered in PEG-400 or 10% solutol/H₂O, at 1.0 or 3.0 mg/kg, i.p.and spontaneous “wet-dog” shakes may be counted 10-20 minutespost-icilin. Results are shown in Table 2.

TABLE 2 % Cpd Form Dose Route Vehicle Inhibition 8 Hydrochloride 10 p.o.10% 15.5 Solutol 38 Hydrochloride 10 p.o. 20% 6.5 HPβCD 107 CO₂ ⁻Na⁺ 10p.o. 20% −20.6 HPβCD 109 CO₂ ⁻Na⁺ 10 p.o. 20% −7.5 HPβCD

Example 2b Reversal of Icilin-Induced Behaviors in Rats

Male Sprague Dawley rats (225-450 g, Charles River Labs,n=4-6/treatment) may be used to evaluate the ability of selectedcompounds of the formula (I) to reverse icilin-induced “wet-dog” shakes.Icilin may be administered in PEG-400 or 10% solutol/H₂O, at 1.0 or 3.0mg/kg, i.p. and spontaneous “wet-dog” shakes (WDS) may be counted 10-20minutes post-icilin. Animals that may exhibit 10 or more shakes may berandomized into treatment groups and may immediately be administeredcompounds of the formula (I) in an appropriate vehicle, such ashydroxypropyl-β-cyclodextrin (HPβCD), methocellulose, 10% Solutol, orH₂O, or the like, and by the appropriate route, such as i.p. or p.o.Spontaneous “wet-dog” shakes may be counted 60-70 minutes after compoundadministration.

Example 3 In Vivo Model of Subacute Inflammatory Pain:Carrageenan-Induced Hyperalgesia

Intraplantar injection of carrageenan into the hind paw of rats causes arobust acute inflammatory response characterized by reddening, swellingand hypersensitivity of the paw to thermal and mechanical stimulitypically peaking 3-6 hours following application and subsiding over the12-24 hours.

Example 3a Rat Carrageenan-Induced Radiant Heat Hypersensitivity

To assess the effect of test compounds of the formula (I) oninflammatory hyperalgesia, radiant heat response latencies may beevaluated 3 hours following intraplantar carrageenan (Lambda, Type IV,200 uL) injection into a single hind paw in male Sprague-Dawley rats.The test compound may be administered either 2 hours prior to or 1 hourfollowing carrageenan injection. The intent is to determine whether thecompound may prevent or retard the hypersensitivity associated with thisinflammogen. Baseline thermal response latencies may be determined priorto any treatment and again 3 hours after carrageenan injection. Percentreversal of hyperalgesia relative to vehicle treatment (% R) may becalculated for both compound treatment paradigms according to thefollowing formula:

% R=(Post compound latency−Post vehicle latency)/((Baseline latency−Postvehicle latency)×100%.

Example 4 In Vivo Model for of Chronic Inflammatory Pain: CompleteFreund's Adjuvant (CFA)-Induced Hyperalgesia

Intraplantar injection of complete Freund's adjuvant (CFA) in rodentsresults in a long-lasting inflammatory reaction, characterized by apronounced hypersensitivity to both thermal and mechanical stimuli. Thishypersensitivity peaks between 24-72 hours following injection and canlast for several weeks. To assess whether test compounds of the formula(I) reverse established hypersensitivity, a 100 μL intraplantarinjection of CFA (suspended in a 1:1 emulsion of saline and heat-killedMycobacterium tuberculosis in mineral oil) can be injected into a singlehind paw of Sprague-Dawley rats (typically males ranging from 150-350g). This paradigm also may be conducted with a multiple dosing or aprophylactic dosing regime designed to alter the course of hyperalgesiadevelopment. This test predicts the analgesic, anti-allodynic andantihyperalgesic effect of numerous effective clinical agents, includingacetaminophen, NSAIDS such as aspirin and ibuprofen, and opioids, suchas morphine.

Example 4a CFA-Induced Paw Radiant Heat Hypersensitivity

Each rat may be placed in a test chamber on a warm glass surface andallowed to acclimate for approximately 10 minutes. A radiant thermalstimulus (beam of light) may then be focused through the glass onto theplantar surface of each hind paw in turn. The thermal stimulus may beautomatically shut off by a photoelectric relay when the paw is moved orwhen the cut-off time is reached (20 seconds for radiant heat at ˜5Amps). An initial (baseline) response latency to the thermal stimulusmay be recorded for each animal prior to the injection of CFA.Twenty-four hours following intraplantar CFA injection, the responselatency of the animal to the thermal stimulus may be re-evaluated andcompared to the animal's baseline response time. Only rats that exhibitat least a 25% reduction in response latency (i.e. hyperalgesia) areincluded in further analysis. Immediately following the post-CFA latencyassessment, test compound or vehicle (usually Solutol, hydroxypropylmethylcellulose, hydroxypropyl beta-cyclodextrin or PEG-400) may beadministered i.p. or p.o. to rats. Post-compound treatment withdrawallatencies may be assessed at fixed time intervals, typically 30, 60 and120 minutes. The percent reversal (% R) of hypersenstivitiy iscalculated according to the following formula:

% Reversal=(Treatment Response−CFA Response)/(Baseline Response−CFAResponse)×100.

Example 4b CFA-Induced Paw Cold Hypersensitivity

Prior to intraplantar CFA injection, mice or rats may be placedindividually in elevated observation chambers having wire mesh floors.Through the mesh floor a series of three applications of acetone(0.04−0.10 mL/application) may be sprayed onto the bottom of the pawusing a multidose syringe device. A positive response can take the formof an abrupt withdrawal and licking of the paw. The cumulative durationof licking may be recorded for each of the three trials which are thenaveraged to give the individual's response. Twenty-four hours followingCFA injection acetone licking durations may be markedly elevatedimplying a hypersensitivity to cooling. Test compounds of the formula(I) can be assessed for its ability to return acetone-evoked paw lickingdurations to pre-CFA levels (typically near zero) following systemicadministration. Percent inhibition is calculated as follows

% Inhibition=[1−(treatment licking duration/vehicle lickingduration)]×100.

Example 5 Chemically-Induced Abdominal Irritant Models of Visceral Pain

A chemical irritant (such as acetic acid, kaolin, bradykinin,phenyl-p-(benzo) quinine, bromo-acetylcholine, or zymosan) may beinjected in mice intraperitoneally, causing a contraction of theabdominal musculature, which is characterized by an elongation of thebody extending through to the hind limbs The number of such responsesmay be quantitated and may be reduced by pretreatment of analgesicagents, thus forming the basis for a screening test (Collier H O et al.Br J Pharmacol Chemother 1968, 32(2): 295-310). This type of abdominalirritant test has been used to predict the analgesic effect of numerousclinically effective agents, the potency of which in the abdominalirritant test parallels the magnitude of the dose needed in the reliefof clinical pain. Such agents include acetaminophen, NSAIDS such asaspirin and ibuprofen, opioids, such as morphine and codeine, and othercentrally acting analgesics, such as tramadol.

One modification of the chemically-induced abdmonial irritant model ofvisceral pain is to pretreat animals with agents known to induceinflammatory responses following intraperitoneal injection (such as LPS,zymosan, or thioglycolate). A small intraperitoneal dose of such aninflammogen, administered hours or days before the acute chemicalirritant challenge, has been shown to increase the number of abdominalcontractions observed (Ribeiro R A, et al. Eur J Pharmacol 2000, 387(1):111-8). While some analgesic agents are effective at mitigating acuteviscerochemical nociception, others, particularly those dependent uponreceptor induction are more effective at preventing or reversing theenhancement of behavioral responses caused by a preconditioninginflammatory stimulus. Because of the up-regulation of the TRPM8receptor in inflammation, TRPM8 antagonists that are effective atreducing the mean number of contractions are predicted to provideanalgesic action in human clinical use.

The ability of compounds of the formula (I) to mitigate chemicalirritant-induced abdominal contractions following a pre-conditioninginflammatory stimulus may be studied as follows. Thioglycolate (3%, w/v,2-3 mL i.p.) may be injected into male CD1 mice (20-40 g, Charles RiverLabs), at a maximum dosage volume of 80 mL/kg, to induce peritonealinflammation. Following a twenty-four hour pre-inflammation period thesemice may be dosed orally with compounds of the formula (I) (30 mg/kg;n=10) or vehicle (HPMC with 2% Tween80; n=9) and then one hour latersubjected to an abdominal irritant challenge of acetic acid (1%, 10mL/kg, i.p.). Immediately following injection of acetic acid, mice maybe placed individually in glass bell jars (approximately 15 cm indiameter) for counting of abdominal contractions over the next 15minutes. The total number of abdominal contractions may be summed foreach treatment group and employed in the following formula to calculatePercent Inhibition (% I):

% I=[1−(test compound contractions/vehicle contractions)]×100.

Example 6 In Vivo Models of Neuropathic Pain

The sciatic nerve is the major sensorimotor innervation of the (hind)leg and foot. Injury to the sciatic nerve or its constituent spinalnerves often results in pain-related behaviors. In rats and mice, tightligation of the L5 spinal nerve with silk suture, partial tight ligationof the sciatic nerve with silk suture or loose ligation of the sciaticnerve with chromic gut suture each result in behaviors reminiscent ofneuropathic pain in humans. These lesions (one per animal) may beperformed surgically in anesthetized rodents. Both the spinal nerve andsciatic nerve lesions result in allodynia, a painful response tonormally innocuous stimuli, and hyperalgesia, an exaggerated response tonormally noxious stimuli. It is important to note that both of thesepain-related behaviors may be evoked by the testing procedures and thatnormal use of the paw (e.g., walking) is relatively uncompromised, apartfrom occasional “guarding” of the paw. Subsequent to the surgery, thesubjects' behaviors, such as grooming, feeding, and weight gain, arenormal, except for hypersensitivity (as defined above) of the affectedpaw.

In addition to induction by nerve damage resulting from accidentaltrauma or surgical procedures, neuropathic pain can also be induced bydiabetes (Fox, A et al., Pain 81:307-316, 1999) or by treatment withchemotherapeutic agents, such as paclitaxel or vincristine (Yaksh, T Let al., Pain 93:69-76, 2001).

Agents that attenuate neuropathic pain in the clinic also are effectivein rodent neuropathic pain models. These agents include the recentlyapproved Cymbalta (Duloxetine, Iyengar, S., et al., JPET 2004311:576-584), morphine (Suzuki, R et al., Pain 1999 80:215-228) andgabapentin (Hunter, J C et al., Eur J Pharmacol 1997 324:153-160). Thedual TRPV1/TRPM8 receptor antagonist BCTC reduced mechanicalhyperalgesia and tactile allodynia in the chronic constriction injuryrodent neuropathic pain model (Pomonis, J D et al., JPET 2003306:387-393; Behrendt, H et al., Brit J Pharm 2004 141:737). Coldallodynia is a particularly debilitating symptom of neuropathic painconditions (Jorum E et al. Pain 2003 101: 229-235). The antiallodyniceffect of compounds of the formula (I) in this rodent model ispredictive of clinical effect for these novel agents.

Example 6a Chronic Constriction Injury (CCI)-Induced Model ofNeuropathic Pain—Acetone-Induced Hypersensitivity

Male Sprague Dawley rats (225-450 g; n=5-8/treatment) may be used toevaluate the ability of selected compounds of the formula (I) to reverseCCI-induced cold hypersensitivity. Four loose ligatures of 4-0 chromicgut may be surgically placed around the left sciatic nerve underinhalation anesthesia as described by Bennett et al (Bennett G J, Xie YK. Pain 1988, 33(1): 87-107). Fourteen to 35 days following CCI surgery,subjects may be placed in elevated observation chambers containing wiremesh floors and five applications of acetone (0.05 mL/applicationseparated by approximately 5 minutes) may be spritzed onto the plantarsurface of the paw using a multidose syringe. An abrupt withdrawal orlifting of the paw may be considered as a positive response. The numberof positive responses may be recorded for each rat over the five trials.Following baseline withdrawal determinations, compounds of formula (I)may be administered in an appropriate vehicle, such ashydroxypropyl-β-cyclodextrin (HP β CD), methylcellulose, Methocel, 10%Solutol, or H₂O, or the like, by the appropriate route, i.p. or p.o. Thenumber of withdrawals may be redetermined 1 to 3 h after compoundadministration. Results may be presented as a percent inhibition ofshakes, which was calculated for each subject as [1-(test compoundwithdrawals/pre-test withdrawals)]×100 and then averaged by treatment.

Example 6b Chronic Constriction Injury (CCI)-Induced Model ofNeuropathic Pain—Cold Plate-Induced Hypersensitivity

In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gut maybe surgically placed around the left sciatic nerve under inhalationanesthesia as described by Bennet et al (Bennett G J, Xie Y K. Pain1988, 33(1): 87-107). Seven to 21 days following sciatic chronicconstriction injury (CCI) surgery, the subjects can be placed onto acommercial cold plate device cooled by peltier elements such that thesurface temperature is held at 1° C. Each subject can undergo a 6 minuteconditioning period followed by a 3 minute assessment period duringwhich the total duration of hind paw lifting is recorded. This procedureis repeated at several intervals prior to and following systemic drugadministration. Compounds of the formula (I) can be assessed for theirability to return duration of paw lifting back to pre-lesion levels. Theduration of paw lifting during the 3 minute test period followingadministration of test compound is taken as a percentage of the durationof paw lifting during the 3 minute test period prior to test compoundtreatment.

Example 6c Chronic Constriction Injury (CCI)-Induced Model ofNeuropathic Pain—Mechanical Allodynia (Von Frey Test)

In male SD rats (175-325 g), four loose ligatures of 4-0 chromic gut maybe surgically placed around the left sciatic nerve under inhalationanesthesia as described by Bennet et al (Bennett G J, Xie Y K. Pain1988, 33(1): 87-107). Seven to 21 days following sciatic chronicconstriction injury (CCI) surgery, the subjects can be placed onto anelevated rack of plexigas chambers having wire mesh or another type ofperforated flooring. The measurement of mechanical allodynia can beperformed using the von Frey hairs (Semmes-Weinstein Monofilaments,Stoelting Co., IL) wherein the rats can be habituated to the wire meshbottom cages before the start of the experiment. Static allodynia can betested in the unrestrained rats by touching the plantar surface of thehind paw with von Frey hairs in ascending order of force (1.2, 1.5, 2.0,3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until a pawwithdrawal response can be elicited. The lowest amount of force requiredto elicit a response can be recorded as the withdrawal threshold in logg. This procedure is repeated at several intervals prior to andfollowing systemic drug administration. Compounds of the formula (I) canbe assessed for their ability to return the threshold force whichelicits paw lifting back to pre-lesion levels.

Example 7 Inflammatory Agent-Induced Models of Pyresis/Antipyresis

Compounds of the formula (I) can be tested in animal models of pyresis,according to previously documented and validated methods, such as thosedescribed by Kozak et al (Kozak W, Fraifeld V. Front Biosci 2004, 9:3339-55). Fever is a frequent accompaniment of inflammatory disease.Animal models make use of the pyretic properties of yeast and otherinflammatory agents, injecting a yeast suspension or other agentsubcutaneously (Tomazetti J et al. J Neurosci Methods 2005, 147(1):29-35); Van Miert A S, Van Duin C T. Eur J Pharmacol 1977, 44(3):197-204). For example, Male Wistar rats (75-100 g) can be housed ingroups of four to a cage at controlled temperature (23±1° C.) with a 12h light:12 h dark cycle (lights on at 07:00 h) and with standard labchow and tap water ad libitum. All measured temperatures can be takenbetween 08:00 and 19:00 h. Each animal can be used in only one study.Rectal temperature (TR) can be measured by inserting a lubricatedthermistor probe (external diameter: 3 mm) 2.8 cm into the rectum of theanimal. The probe can be linked to a digital device, which displayed thetemperature at the tip of the probe with a 0.1° C. precision and logsthe values over time. Immediately after measuring the initial basalrectal temperature, the animals can be injected with commerciallyavailable dried baker yeast (Saccharomyces cerevisiae) suspended inpyrogen-free 0.9% NaCl (0.05-0.25 g/kg, i.p.) or 0.9% NaCl (10 ml/kg).TR changes can be recorded every hour up to 12 h, and expressed as thedifference from the basal value. Since it has been previously reportedthat handling and temperature measuring-related stress alter rectaltemperature, these animals can be habituated to the injection andmeasuring procedure for 2 days before experiments are carried out. Inthese sessions, the animals can be subjected to the same temperaturemeasuring procedure described above, and can be injectedintraperitoneally (i.p.) with 0.9% NaCl (10 ml/kg).

To assess the effect of potential antipyretic compounds on basal rectaltemperature study animals can have their TR measured for 4 h, and afterthe fourth TR measurement they can be subcutaneously (s.c.) injectedwith vehicle (such as 10% Solutol in sterile water 5 ml/kg) or compoundsof the formula (I) prepared in vehicle. TR can then be recorded everyhour up to 8 h after the compound injections. To assess the effect ofcompounds of the formula (I) on baker yeast-induced hyperthermia, studyanimals can have their basal TR measured and then be injected with apyrogenic dose of baker yeast (for example, 0.135 g/kg). TR changes canbe recorded every hour up to 4 h, when potential antipyretics agentssuch as those compounds of the formula (I) are administered. Rectaltemperature can then be monitored over the following 8 h. Basal rectaltemperature and changes in rectal temperature can be expressed asmeans±S.E.M. of the differences from TR at 07:00 h. Data can be analyzedby two-way analysis of variance (ANOVA), with time of measures treatedas within subject factor, depending on the experimental design. Post hocanalysis can be carried out by the F-test for simple effect and theStudent-Newman-Keuls test, when appropriate. A value of P<0.05 would beconsidered statistically significant.

The modification of the subsequent pyretic response by therapeuticagents can also be monitored by rectal telemetry or other measurementsof body temperature. Several clinically relevant agents such asacetaminophen, aspirin and ibuprofen, reduce fever in these models. Theantipyretic effect of TRPM8 antagonists, such as compounds of theformula (I), in these tests would also be predictive of their clinicaleffect.

Example 8 CFA-Induced Model of Rheumatoid Arthritis

Compounds of the formula (I) can be tested in animal models ofrheumatoid arthritis, according to previously documented and validatedmethods, such as those described by Nagakura et al (Nagakura Y, et al. JPharmacol Exp Ther 2003, 306(2): 490-7). For example, arthritis can beinduced by the CFA inoculation in the rats (Male Lewis rats 150-225 g;Charles River). Briefly, 100 mg of Mycobacterium butyricum (Difco,Detroit, Mich.) can be thoroughly mixed with 20 mL of paraffin oil. Thenmixture can be autoclaved for 20 min at 120° C. Each rat can be injectedin the right footpad (hind paw) with the mixture in a 0.1-mL volumeunder inhalation anesthesia. The rats serving as controls can beinjected with 0.1 mL of saline. Pain and other disease developmentparameters can be measured in the CFA- or saline-treated rats justbefore inoculation and up to 28 days post-inoculation. The measurementfor pain parameters can be conducted for both mechanical and thermal(hot or cold) endpoints. The measurement of mechanical allodynia can beperformed using the von Frey hairs (Semmes-Weinstein Monofilaments,Stoelting Co., IL) wherein the rats can be habituated to wire meshbottom cages before the start of the experiment. Static allodynia can betested in the unrestrained rats by touching the plantar surface of thehind paw with von Frey hairs in ascending order of force (1.2, 1.5, 2.0,3.6, 5.5, 8.5, 12, 15, 29, and 76 g) for up to 6 s or until a pawwithdrawal response can be elicited. The lowest amount of force requiredto elicit a response can be recorded as the withdrawal threshold in logg. Thermal hyperalgesia can be assessed using the radiant heat testwherein a mobile radiant heat source can be located under a glasssurface upon which the rat is placed. The beam of light can be focusedon the hind paw, and the paw withdrawal latencies are defined as thetime taken by the rat to remove its hind paw from the heat source. Themeasurement of joint hyperalgesia can be performed by a modification ofthe previously reported method (Rupniak N M J et al. Pain 1997, 71:89-97). The torso of each rat can be held from the back with the leftpalm, and the bending and extension (one after the other and five timesin each direction) of the ankle within its limits of range of motion canbe performed with the right fingers. The total number of vocalizationsemitted after the manipulation (the bending and extension, five times ineach direction) can be recorded for each paw (the maximum score is 10for each paw).

The scoring of mobility can be performed by modifying the evaluationscale reported by Butler et al. (Butler S H et al Pain 1992, 48: 73-81):score 6, walks normally; score 5, walks being protective toward theipsilateral hind paw (touches the ipsilateral hind paw fully on thefloor); score 4, walks being protective toward the ipsilateral hind paw(touches only the toe of the ipsilateral hind paw on the floor); score3, walks being protective toward both hind paws (touches thecontralateral hind paw fully on the floor); score 2, walks beingprotective toward both hind paws (touches only the toe of thecontralateral hind paw on the floor); score 1, crawls only using thefore paws; and score 0, does not move. Paw volumes can be measured byvolume displacement of electrolyte solution in a commercially availableplethysmometer device. The hind paw can be immersed to the junction ofthe hairy skin, and the volumes can be read on a digital display. Thescoring of joint stiffness can be performed as follows: the body of ratscan be held from the back with the left palm, and the bending andextension (once in each direction) of the ankle within its limits ofrange of motion can be performed with the right fingers. It can beconfirmed beforehand that there is no restriction of ankle jointmovement in the bending and extension manipulations in naive rats, andthe scoring can be performed according to the evaluation scale reportedby Butler (Butler S H et al Pain 1992, 48: 73-81): score 2, there arerestrictions of full range of movement of the ankle in both bending andextension; score 1, there is a restriction of full range of movement ofthe ankle in bending or extension; and score 0, no restriction. Themeasurements for paw volume and joint stiffness can be conducted forboth hind paws.

Compounds of the formula (I) can be assessed for antihyperalgesicefficacy as follows: thirty-two rats (8 rats per dose and four doses percompound) that are be treated with the CFA and another eight rats asnaive controls can be used for each drug evaluation. The analgesiceffects can be evaluated on post-inoculation day 9, when mechanicalallodynia, thermal hyperalgesia, joint hyperalgesia, and joint stiffnessin the ipsilateral paw reached almost the maximum, although thoseparameters in the contralateral paw changed only slightly and thesystemic disturbance shown by the change of mobility score is small. Onthe day before evaluation, body weight, mechanical allodynia, thermalhyperalgesia, and joint hyperalgesia can be measured for the 32 ratsthat are to be used for compound evaluation. The rats are allocated tofour groups (eight rats per group) such that the differences in theaverages of those parameters among the groups became small. All theanalgesic effect evaluations and behavioral observations can be carriedout by the observer who is blind to the drug treatment.

Data can be expressed as the mean+/−S.E.M. The time-course curves formechanical allodynia, thermal hyperalgesia, joint hyperalgesia, bodyweight, and paw volume can be subjected to two-way repeated measuresanalysis of variance with post hoc t test. In experiments for evaluationof compounds of formula (I), the difference in scores between thevehicle-treated and naive control groups can be analyzed by Student's ttest to confirm significant changes in the pain parameters in theipsilateral paw. The analgesic effects can be analyzed by Dunnett's ttest, and in each case the drug-treated groups can be compared with thevehicle-treated group. In each statistical analysis, the comparison canbe conducted for paws on the corresponding side. P<0.05 is consideredstatistically significant. In this model, the centrally actinganalgesics morphine and tramadol fully relieved pain, whereas theNSAIDs, indomethacin and diclofenac are partially effective, evidencingthe model's clinical predictability. The analgesic effect of compoundsof the formula (I) in this test would predict their clinical usefulnessin treating arthritis.

Example 9 In Vivo Model for Arthritis: Inflammogen-Induced Hyperalgesiaof the Knee Joint

Compounds of the formula (I) can be tested in animal models ofosteoarthritis, according to previously documented and validatedmethods, such as those described by Sluka et al (Sluka K A, Westlund KN. Pain 1993, 55(3): 367-77). For example, male Sprague-Dawley rats(Harlan, Indianapolis, Ind.) weighing 225 to 350 g can be brieflyanesthetized with vaporized halothane and then injected with a mixtureof 3% carrageenan and 3% kaolin (100 μL in 0.9% sterile saline) into thejoint cavity of one knee. After the injection, the animals can bereturned to their cages until the time of testing. For behavioraltesting animals can be placed in individual clear plastic cages on topof an elevated wire mesh surface that restricted movement. The animalsshould be allowed to acclimate for approximately 1 hour before testing.Von Frey filaments, as described above, can then be used to test forenhanced responses to mechanical stimuli. The filaments can besuccessively applied through the wire mesh perpendicularly to theplantar surface in between the pads of the third and fourth phalanges.The response threshold to mechanical stimuli can be determined beforeinflammation of the knee joint; 4 hours after inflammation to confirmthe development of hyperalgesia; immediately after the administration oftest compound such as those of Formula (I) i.e. 5 hours afterinflammation; and at 8, 12, and 24 hours after inflammation.

The Kruskal-Wallis test, a nonparametric test, can be used to analyzethe effects for frequency, intensity, and group for response tomechanical stimuli at baseline, 4 hours after inflammation, and aftercompound treatment (5 hours, 8 hours, 12 hours, and 24 hours afterinflammation). Further post hoc testing between groups can be executedby using the Mann-Whitney signed rank test. The data can be presented asmedian with 25th and 75th percentiles. Significance is P≦0.05.

Additionally, the gait of the animal or other pain-related behavior canbe scored as the dependent measure of the painful effect of thearthritis on the animal's activity (Hallas B, Lehman S, Bosak A, et al.J Am Osteopath Assoc 1997, 97(4): 207-14). The effect of test drug onthe animal's normal behavior can be quantified from zero, meaning noresponse, to three for incapacitating impairment. Effective analgesictreatment includes the clinically used indomethacin (Motta A F, et al.Life Sci 2003, 73(15): 1995-2004). Thus the benefit of compounds of theformula (I) in this model would predict their clinical relevance.

Example 10 Sarcoma Cell-Induced Models of Bone Cancer Pain

Compounds of the formula (I) can be tested in animal models of bonecancer pain, according to previously documented and validated methods,such as those described in the scientific literature (El Mouedden M,Meert T F. Pharmacol Biochem Behav 2005, 82(1): 109-19; Ghilardi J R, etal. J Neurosci 2005, 25(12): 3126-31). In preparation for cellinoculation and tumor induction, osteolytic murine sarcoma cells (NCTC2472, American Type Culture Collection (ATCC), Rockville, Md., USA) canbe cultured in NCTC 135 medium (Invitrogen) containing 10% horse serum(Gibco) and passaged 2 times weekly according to ATCC guidelines. Fortheir administration, cells can be detached by scraping and thencentrifuged at 1000×g. The pellet can be suspended in fresh NCTC 135medium (2.5×10⁶ cells/20 μL) and then used for intramedullary femurinoculation. Male C3H/HeNCrl mice (25-30 g, Charles River Labs) can beused in such experiments. After induction of general anesthesia withxylazine (10 mg/kg i.p.) and ketamine (100 mg/kg i.p.) the left hind pawcan be shaved and disinfected with povidone—iodine followed by 70%ethanol. A superficial incision of 1 cm can then be made over the kneeoverlaying the patella. The patellar ligament can then be cut, exposingthe condyles of the distal femur. A 23-gauge needle can be inserted atthe level of the intercondylar notch and the intramedullary canal of thefemur to create a cavity for injection of the cells. Twenty microlitersof media (sham animals) or media containing tumor cells (approximately2.5×10⁶ cells) can then be injected into the bone cavity using asyringe. To prevent leakage of cells outside the bone, the injectionsite can be sealed with dental acrylic and the wound closed with skinstitches.

Pain behaviors can be evaluated in separate groups (n=6) of sham andbone tumor mice with confirmed hyperalgesia as assessed by spontaneouslifting behavior. Animals can be behaviorally tested during a 3-weekperiod prior to and after tumor inoculation. Body weight of the mice canbe recorded throughout the experimental period to help monitor generalhealth status. To measure the spontaneous lifting, the animals can behabituated in a transparent acrylic cylinder of 20 cm diameter put on anhorizontal surface and thereafter observed during 4 min for spontaneouslifting behavior of the left hind paw. After spontaneous liftingbehavior assessment, animals can be immediately placed on a mouserotarod (e.g. ENV-575M\, Med Associates Inc., GA, USA) at a speed of 16rpm for 2 min wherein limb-use during forced ambulation is scored:4=normal; 3=limping; 2=partial non-use of left hind paw; 1=substantialnon-use of left hind paw; 0=non-use of left hind paw. Assessment of coldallodynia may be made by exposing the ipsilateral hind paw of the mouseto 5 repeated applications of acetone (20 μL) and quantifying thelift/licking frequency and/or duration. Post-mortem evaluation of bonedestruction can be assessed by ACT processing followed by scanning usinga system such as the Skyscan 1076 microtomograph system for small animalimaging (Skyscan 1076\, Skyscan, Aartselaar, Belgium). Measuredhistomorphometry parameters of bone destruction can be subsequentlycorrelated with behavioral endpoints.

The antihyperalgesic, antiallodynic and disease modifying effects ofcompounds of the formula (I) can be tested in this murine model of bonecancer pain in separate groups (n=6 per dose group). Animals withconfirmed hyperalgesia, as assessed by spontaneous or acetone-evokedlifting, can be behaviorally tested, for example, on days 15 and 22after distal femur tumor inoculation before and 1 h after systemicadministration of vehicle (e.g. 20% HPbCD in sterile water) or compoundsof the formula (I). The statistical analysis can be performed by one-wayANOVA to compare behavioral measurements and bone parameters among theexperimental groups. To compare behavioral measurements and boneparameters between sham and tumor-bearing animals, a Mann-Whitney U testcan be used. Results are considered statistically significant at P<0.05(two-tailed). Data are expressed as mean+/−S.E.M.

Bone cancer causes intense pain in humans, mimicked in animal models ofbone cancer pain in rodents such as that described above. Analgesictreatments that are effective in this model include COX-2 inhibitors(Sabino M A, Ghilardi J R, Jongen J L, et al. Cancer Res 2002, 62(24):7343-9) and high doses of morphine (Luger N M et al. Pain 2002, 99(3):397-406), agents used clinically for pain relief in patientsexperiencing bone cancer pain. Because this model so closely mimics thehuman disease state, the finding that cold allodynia is a prominentsymptom (Lee, Seong et al. Yonsei Med J 2005, 46(2): 252-9) stronglysupports the concept that TRPM8 antagonists of the present inventionwill provide relief of pain associated with human bone cancer.

Example 11 Respiratory Irritant-Induced Models of Cough

Compounds of the formula (I) can be tested in animal models ofantitussive activity, according to previously documented and validatedmethods, such as those described by: Tanaka, M. and Maruyama, K. JPharmacol. Sci 2005, 99(1), 77-82; Trevisani, M. et al., Throax 2004,59(9), 769-72; and Hall, E. et al., J Med. Microbiol 1999, 48: 95-98.Testing is conducted in transparent ventilated chambers with a constantairflow of 400 mL/min. The tussive agent (citric acid 0.25 M orcapsaicin 30 mM) can be nebulised via a miniultrasonic nebuliser with anoutput of 0.4 mL/min. The appearance of cough can be detected by meansof a tie clip microphone and confirmed by the characteristic posture ofthe animal. The cough sounds can be recorded and digitally stored. Ablinded observer subsequently counts the number of elicited coughefforts. In some cases, animals can be sensitized by pre-exposure tocertain agents such as ovalbumin. A test compound can be administered toat the peak of irritant-induced cough to evaluate the antitussiveeffects of the compound. In addition, prophylactic or multiple dosingregimes can be utilized to evaluate the test compound for modulation ofthe onset and duration of irritant-induced cough. Variations of thesetests predict the antitussive effects of effective clinical agents,including NMDA antagonists such as dextrorphan and dextromethorphan,opioids such as codeine, beta 2 agonists such as salbutamol andantimuscarinics such as ipratropium (Bolser, D. C. et al., Eur JPharmacol 1995, 277(2-3), 159-64; Braga, P. C. Drugs Exper Clin Res1994, 20, 199-203). The antitussive action of menthol in both guinea pigand humans Eccles R. Curr Allergy Asthma Rep 2003, 3(3): 210-4; Laude EA, et al. Pulm Pharmacol 1994, 7(3): 179-84; Morice A H, et al. Thorax1994, 49(10): 1024-6) is predictive of the clinical utility of compoundsof the formula (I) as antitussive agents.

Example 12 Chemical Irritant-Induced Models of Itch, Contact Dermatitis,Eczema and Other Manifestations of Dermal Allergy, Hypersensitivityand/or Inflammation

Compounds of the formula (I) can be tested in animal models of contactdermatitis or itch, according to previously documented and validatedmethods, such as those described in the scientific literature(Saint-Mezard P et al. Eur J Dermatol 2004, 14(5): 284-95; Thomsen J.S., et al. J Exp Dermatol 2002, 11(4): 370-5; Weisshaar E, et al. ArchDermatol Res 1998, 290(6): 306-11; Wille J J, et al. Skin Pharmacol ApplSkin Physiol 1999, 12(1-2): 18-27). Mice (or species such as guinea pigor rat) can be sensitized with 25 mL of 0.5% dinitrofluorobenzenesolution (DNFB diluted 4:1 in acetone:olive oil immediately beforeapplication or other haptens, such as 12-myristate-13 acetate, picrylchloride, oxazolone, capsaicin, arachidonic acid, lactic acid,trans-retinoic acid or sodium lauryl sulfate) painted to the shaveddorsal skin or untreated (controls). Five days later, 10 mL of 0.2% DNFBa nonirritant dose) can be applied onto both sides of the right ear andthe same amount of solvent alone onto the left ear. Ear thickness can bemonitored daily using a caliper. Compounds of the formula (I) can beadministered at the peak of inflammation to evaluate the anti-allergyactivity of compounds. In addition, prophylactic or multiple dosingregimes can be utilized to evaluate the test compound for modulation ofthe onset and duration of anti-allergy activity. Variations of thesetests can predict the anti-allergy and itch activity of effectiveclinical agents. The ability of these models to predict the therapeuticeffect of compounds in human dermal conditions is supported by thecross-species ability of serotonin to induce itch (Weisshaar E, GollnickH Skin Therapy Lett 2000, 5(5): 1-2,5). Additionally, the contactsensitizing property of commercially important drugs and the ability ofion channel modulators to prevent and treat skin sensitization in thesemodels (Kydonieus A, et al., Proceedings of the International Symposiumon Controlled Release of Bioactive Materials 24^(th): 23-24, 1997)demonstrate the therapeutic utility of compounds of the formula (I) indermal sensitization.

Example 13 Chemical Irritant-Induced Models of Rhinitis and OtherManifestations of Nasal Hypersensitivity and/or Inflammation

Compounds of the formula (I) can be tested in animal models of rhinitis,according to previously documented and validated methods, such as thosedescribed in the scientific literature (Hirayama Y, et al. Eur JPharmacol 2003, 467(1-3): 197-203; Magyar T, et al Vaccine 2002,20(13-14): 1797-802; Tiniakov R L, et al. J Appl Physiol 2003, 94(5):1821-8). Testing can be conducted in mouse, guinea pig, dog or human inresponse to intranasal challenge with one or more irritants such as coldair, capsaicin, bradykinin, histamine, pollens, dextran sulfate,2,4-tolylene diisocyanate, Bordetella bronchiseptica, Pasteurellamultodica or acetic acid. In some cases, animals can be sensitized bypre-exposure to certain agents including, but not limited to, ragweed orovalbumin. Prior to or following irritant administration, the testsubject can receive, respectively, the prophylactic or therapeuticadministration one or more times of compounds of the formula (I), orvehicle control, by the enteral or parenteral route. Significantdifferences indicative of nasal rhinitis or sensitization for the testcompound-treated subjects compared with vehicle-treated subjects can betaken as evidence of anti-rhinitis activity. Independent variablesinclude dose, frequency and route of administration, time intervalbetween prophylactic or therapeutic test compound administration andirritant challenge as well as sex and non-sex genotype of the testsubject. The intimate role of neurogenic inflammation in thesehypersensitivity states demonstrates that compounds of the formula (I)desensitize or block the sensitization underlying these disease states.

Example 14 Conflict-Induced Models of Anxiety, Panic Disorder and OtherNon-Adaptive Stressful or Phobic Responses

Compounds of the formula (I) can be tested in animal models of anxiety,panic disorders and other non-adaptive responses, according topreviously documented and validated methods, such as those described byCryan and Holmes (Cryan J F, Holmes A. Nat Rev Drug Discov 2005, 4(9):775-90) or Braw et. al. (Y. Braw et al. Behav Brain Res 2006, 167:261-269). Specifically, for studies in rats, the following apparati maybe utilized: an open-field arena (62 cm×62 cm) enclosed by opaque walls(30 cm high) and plus-maze consists of two open arms, 50 cm×10 cm, andtwo enclosed arms, 50 cm×10 cm×40 cm with an open roof, arranged suchthat the two arms of each type are opposite each other. The maze iselevated to a height of 70 cm. The walls of the enclosed arms are madefrom black Plexiglas, while the floors from white Plexiglas. Videotaperecordings can be analyzed using the ‘Observer’ system (NoldusInformation Technology). A subject rat can be removed from its homecage, weighed and placed gently in the center of the open-field arena.The rat can be allowed to explore the open-field freely while itsbehavior is videotaped for 5 min. Afterwards, it can be transferred tothe plus-maze and placed at the center, facing a closed arm. The rat'sbehavior can again be videotaped for 5 min, after which it can bereturned to its home cage. The apparatus can cleaned using a 70% ethanolsolution between rats.

Open-field and plus-maze measures can be grouped into two behavioralclasses, namely ‘anxiety-like behaviors’ and ‘activity’. Open-fieldbehavioral measures may include 1) Anxiety measures: % time in centersquare, % number of entries to center square (from total squaresentered), % time freezing, latency to first freezing (freezing is scoredwhen the subject is in an immobile state for at least 3 seconds; and 2)Activity measures: Total squares entered, number of rearings (standingon two hind legs), latency for first rearing. Plus-maze measures mayinclude 1) Anxiety: % time in open arms, % number of entries to openarms (from total entries), number of unprotected head dips, latency toenter open arm; and 2) Activity: Total entries to all arms. Anxiety-likebehaviors and activity can be analyzed by one-way ANOVA's on each of themeasures, for each the between-subject comparisons. Plus-maze analysescan be conducted in a similar fashion.

Testing may also be conducted in mouse or rat in this fashion in orderto measure avoidance of other aversive environmental stimuli such asGeller or Vogel anticonflict tests, the light/dark test and thehole-board test (see Cryan J F, Holmes A. Nat Rev Drug Discov 2005,4(9): 775-90). Prior to environmental exposure, the test subject canreceive the prophylactic administration one or more times of compoundsof the formula (I), or vehicle control (e.g. 10% Solutol in sterilewater), by the enteral or parenteral route. The cumulative time ornumber of times spent engaged in the aversive behavior can be measured.Significant differences in one or more of these measures for the testcompound-treated subjects compared with vehicle-treated subjects can betaken as evidence of anxiolytic activity. Because these models arepharmacologically validated by the effectiveness of clinically usefulanxiolytics (Cryan J F, Holmes A. Nat Rev Drug Discov 2005, 4(9):775-90), they will be useful for the detection of anxiolytic compoundsof the formula (I).

Example 15 Bladder Pressure- and Hypertrophy-Induced Models of UrinaryIncontinence

Compounds of the formula (I) can be tested in animal models of urinaryincontinence according to previously documented and validated methods,such as those described by in the scientific literature (Kaiser S, PlathT, (Metagen Pharmaceuticals GmbH, Germany DE Patent 10215321; McMurrayG, et al. Br J Pharmacol 2006, 147 Suppl 2: S62-79). TRPM8 is expressedin human prostate, testicle, seminiferous tubules, scrotal skin andinflamed bladder (Stein R J, et al. J Urol 2004, 172(3): 1175-8; Stein RJ, et al. J Urol 2004, 172(3): 1175-8; Mukerji et al. BMC Urology 2006,6:6). Excitation of TRPM8 receptors through cooling or application ofmenthol causes contraction in the bladder and a decrease in micturationthreshold volume (Tsukimi Y, Mizuyachi K, et al. Urology 2005, 65(2):406-10). To assess compounds of the formula (I) for potential urinaryincontinence activity, Sprague-Dawley rats are surgically implanted withbladder catheters allowing for the delivery of fluid (typically saline)and the monitoring of pressure (using a pressure transducer). Cystometryrecordings can be monitored with a polygraph to evaluate voidinginterval, threshold pressure, bladder capacity, bladder compliance, andthe number of spontaneous bladder contractions. For example, the bladdercatheter can be connected to a Harvard infusion pump, and bladdersperfused overnight with saline at 2 mL/h. The next morning the bladdercatheter can be attached (using a “T” connector) to a Statham pressuretransducer (Model P23Db) and to a Harvard infusion pump. A plasticbeaker attached to a force displacement transducer (Grass FTO3) can beplaced under the rat's cage to collect and record urine volume. Thecystometric evaluation of bladder function can be started by infusingsaline (20 mL/h) and after the first micturition the infusion ismaintained for 20 min. Two hours after the first cystometry period, therats can be dosed orally with compounds of the formula (I) and a secondcystometry is performed between 30 min and 4 h after administration oftest compound. The appropriate vehicle (e.g. 10% Solutol in sterilewater) can be similarly administered to groups of rats that served ascontrols and the cystometry can be performed at the same respective timepoints.

Compounds of the formula (I) can also be evaluated under conditions ofbladder hypertrophy and instability. Under anesthesia, a silk ligatureis tied around the proximal urethra of rodents producing a partialoutlet obstruction and subsequent hypertrophied bladder developmentwithin 6-9 weeks (Woods M. et al., J Urology 2001, 166:1142-47).Cystometry recordings can then be evaluated as described above. Suchpreclinical procedures are sensitive to compounds having clinicalutility for the treatment of urinary incontinence (Soulard C, et al. JPharmacol Exp Ther 1992, 260(3): 1152-8), and the activity of compoundsof the formula (I) in this model would be predictive of clinicalutility.

Example 16 In Vivo Model for Cold-Enhanced Central Pain States

Injury to the brain or spinal cord, such as that caused by trauma,interrupted blood flow or neurodegenerative diseases, often precipitatesa central pain condition. Examples of such injuries characterized, inpart by, a hypersensitivity to cold stimuli include multiple sclerosis(Morin C, et al. Clin J Pain 2002, 18(3): 191-5; Svendsen K B, et al.Pain 2005, 114(3): 473-81), stroke or cerebral ischemia (Greenspan J D,et al. Pain. 2004, 109(3): 357-66) and spinal cord injury (Defrin R,Ohry A, Blumen N, Urca G. Pain 2001, 89(2-3): 253-63; Defrin R, et al.Brain 2002, 125(Pt 3): 501-10; Finnerup N B, et al. Anesthesiology 2005,102(5): 1023-30). Each of these conditions may be readily modeled inanimals for assessment of the ability of compounds of the formula (I) tomollify the hypersensitive state. For example, a spinal cord injury(SCI) can be performed in adult Sprague-Dawley rats having a body weightof 150-200 g at time of surgery (Erichsen et al. Pain 2005, 116:347-358). The rats can be anaesthetized with chloral hydrate (300 mg/kg,i.p., Sigma, USA) and a catheter can be inserted into the jugular vein.A midline skin incision can then be made along the back to expose theT11-L2 vertebrae. The animals can be positioned beneath a tunable argonion laser (Innova model 70, Coherent Laser Products Division, Calif.,USA) operating at a wavelength of 514 nm with an average power of 0.17W. The laser light can be focused into a thin beam covering the singleT13 vertebra, which can be irradiated for 10 min. Immediately before theirradiation, erythrosin B (Aldrich, 32.5 mg/kg dissolved in 0.9% saline)can be injected intravenously via the jugular catheter. Due to rapidmetabolism of erythrosin B, the injection can be repeated after 5 min inorder to maintain adequate blood concentrations. During irradiation, thebody core temperature can be maintained at 37-38° C. by a heating pad.After irradiation the wound can be closed in layers and the skin suturedtogether.

SCI rats can be routinely tested for the presence of pain-like behaviorsfrom 3-4 weeks after surgery. The fur of the animals can be shaved atleast a day prior to examination of the cutaneous pain threshold toavoid sensitization of the skin receptors. During testing, the rats canbe gently held in a standing position by the experimenter and the flankarea and hindlimbs can be examined for hypersensitivity to sensorystimulation. On the day of drug testing, SCI rats can be administereddrug according to the experimental schedule and the time course ofpain-like behaviors can be measured. To test for the presence of coldallodynia, ethyl chloride or acetone can be sprayed onto the skin of theanimals, often that which has been previously determined to be sensitiveto mechanical stimulation by von Frey filament testing. The subsequentresponse to cold stimulation can be observed and classified according tothe following scale: 0, no visible response; 1, localized response (skintwitch) without vocalization; 2, transient vocalization; 3, sustainedvocalization. Kruskal Wallis ANOVA on ranks can be used to analyze theoverall effects of non-parametric data obtained in response to coldstimulation following pretreatment with either compounds of the formula(I) or vehicle.

Example 17 In Vivo Model for Post-Anesthetic Shivering

Spontaneous post-anesthetic tremor that resembles shivering is commonduring recovery from anesthesia. Risks to postoperative patients includean increase in metabolic rate of up to 400%, hypoxemia, wounddehiscence, dental damage, and disruption of delicate surgical repairs.The etiology of spontaneous post-anesthetic tremor is most commonlyattributed to normal thermoregulatory shivering in response tointraoperative hypothermia. In most operating and recovery rooms,shivering is controlled by the use of humidifiers, warming blankets, andinhalation of humidified heated oxygen. However, pharmacological controlis an effective alternate treatment modality (Bhatnagar S, et al.Anaesth Intensive Care 2001, 29(2): 149-54; Tsai Y C, Chu K S. AnesthAnalg 2001, 93(5): 1288-92). Compounds of the formula (I) may beassessed for their ability to mitigate post-ansethetic induced-shakingby using animal models such as that described by Nikki et al (Nikki P,Tammisto T. Acta Anaesthesiol Scand 1968, 12(3): 125-34) and Grahn(Grahn, D A, et al. J Applied Physiology 1996, 81: 2547-2554). Forexample, Wistar rats (males, weighing 250-450 g) may be surgicallyimplanted with an EEG/EMG recording array to assess post anesthetictremor activity. The EEG electrodes are located bilaterally 2 mm offmidline and adjacent to bregma and lamda. Following a one-week recoveryperiod, frontal-occipital EEG, raw EMG, and integrated EMG activities,as well as three temperatures (skin, rectal, and water blankettemperatures during anesthesia), and ambient temperature post-anesthesiacan be monitored throughout the experiment using copper-constantinthermocouples. The EEG and EMG signals can be recorded on polygraphpaper (5 mm/s, Grass model 7E polygraph) and, during recovery fromanesthesia, the EEG is computer scored in 10 second epochs as eithersynchronized: high amplitude (0.100 μV), low frequency (1-4 Hzdominated) activity characteristic of slow-wave sleep (SWS-like) ordesynchronized: low amplitude (75 μV), high frequency (5-15 Hzdominated), characteristic of waking and rapid-eye-movement sleep(W-like). The EMG activity can be quantified as the averaged summedvoltage/time interval by processing the raw EMG signal through anintegrator (Grass model 7P3, 0.5 s time constant). On the day of anexperiment, the animal can be placed in a small acrylic box (15×15×15cm) and exposed to a halothane vapor-air mixture (4% halothane).Immediately after the induction of anesthesia, the animal can be removedfrom the enclosure and subsequently anesthetized through a nose cone.Following cessation of anesthesia, two stages of recovery can be judged:emergence from anesthesia and restoration of behavioral activity(behavioral recovery). Emergence from anesthesia may be defined as anincrease in tonic EMG activity and a change in the EEG from a SWS-likepattern to a W-like pattern. Behaviorally, recovery has occurred whenthe animal rises from a prone position and initiated coordinatedmovements. The time intervals from termination of anesthesia toemergence and behavioral recovery can be measured in all animals. Timeinterval data can be subjected to a repeated measure analysis ofvariance, and the Scheffe's method can be employed for testingdifferences between pairs of means.

Example 18 Cold-Evoked Cardiovascular Pressor Responses

Compounds of the formula (I) can be tested in animals and humans fortheir ability to mitigate cardiovascular pressor responses evoked bycold exposure. Seasonal environmental cooling is directly associatedwith elevated blood pressure and an increased incidence of coronaryevents in human populations worldwide (Barnett, A G et al. J EpidemiolCommunity Heath 2005, 59 551-557). Cold-evoked pulmonary hypertentionand cold aggravation of chronic obstructive pulmonary disease areclinical indications succeptible to heightened cardiopulmonarysensitivity to cold (Marno P et al. Eur Respiratory Review 2006, 15(101): 185.; Acikel M et al Int J of Cardiol (2004) 97: 187-192). Theclinical cold pressor test assesses changes in blood pressure (BP) andcold pain perception during a 2-3 minute immersion of one hand into icewater. This test may be utilized to characterize analgesic compounds(Koltzenberg M et al. Pain 2006, 126(1-3): 165-74) and to assess coldhypersensitivity (Desmeules J A et al. Arthritis Rheum 2003, 48(5):1420-9). Compounds of the formula (I) can be studied in an anesthetizedrat cold pressor paradigm to determine whether TRPM8 antagonism wouldinterfere with the blood pressure pressor response to cold stimulationof the forepaws. Male Sprague-Dawley rats (300-450 g) anesthetized withsodium pentobarbital are instrumented with a jugular catheter and anindwelling carotid artery cannula connected to a pressure transducer.Vehicle (e.g. 20% HPbCD in sterile water) or test compound is infused (1mL/kg) over one minute through the intravenous catheter. Ten minuteslater both forelimbs are packed in crushed ice for 5 minutes.Alternatively, the test compound and vehicle treatments may beadministered orally at an appropriated time prior to the surgicalcannulations and cold challenge. Percent changes in mean arterialpressure in response to this cold stimulus are calculated for vehicleand test compound pretreatments. Percent inhibition attributed totreatment with test compound is then determined using the followingformula: % Inhibition=[1−(cold evoked % change in BP post-testcompound/cold evoked % change in BP post-vehicle)]×100.

Example 19 Cold-Induced Vasoconstriction: Ramifications for TissuePerfusion

Damage may occur to a bodily tissue when blood flow is compromised orinterrupted. Reasons for vascular compromise include peripheral vasculardisease (Lamah M et al, European journal of vascular and endovascularsurgery (1999), 18(1), 48-51), prior traumatic or frostbite injury,Raynaud's syndrome (Lutolf, O et al Microvascular research (1993),46(3), 374-82), diabetic neuropathy (Forst T et al, Clinical science(London, England: 1979) (1998), 94(3), 255-61.), surgical interventionand autonomic dysregulation (Gherghel D et al, Investigativeophthalmology & visual science (2004), 45(10), 3546-54). In the case ofmarginal resting perfusion, vasoconstriction as enchanced by cooltemperature may aggravate symptoms and potentiate tissue injury (CankarK et al, The Journal of hand surgery (2000), 25(3), 552-8; Lutolf 0 etal Microvascular research (1993), 46(3), 374-82.). Several of theseconditions may be readily modeled in animals to assess of the ability ofTRPM8 antagonists such as compounds of the formula (I) to preservetissue perfusion in the face of local cooling. For example, laserDoppler assessment of skin blood flow may be studied in the paws ofanesthetized rats (Hord A H et al, Anesthesia and analgesia (1999),88(1), 103-8), wherein the paw is subject to a series of decreasingtemperatures steps as applied by physical contact with a Peltier coolingelement under computer control. The laser Doppler measures skinperfusion in the face of cooling—induced vasoconstriction therebygenerating a temperature×perfusion relationship. Systemic administrationof a TRPM8 antagonist is anticipated to shift this curve towardpreserving perfusion at reduced temperatures relative to vehiclepretreatment. This activity is envisioned to be therapeutic inprotecting tissue from hypo-perfusion and ischemia thereby minimizingthe associated symptoms (e.g. pain) and potential tissue damage.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1.-18. (canceled)
 19. A method for treating a disease, disorder, orcondition that is affected by the modulation of TRPM8, comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a TRPM8 antagonist of Formula (I)

wherein Y is selected from the group consisting of hydrogen, bromo,chloro, C3-6 cycloalkyl, and C1-6 alkyl; R1 is i) C1-6alkyl whereinC1-6alkyl is unsubstituted or substituted with one substituent that isC3-6cycloalkyl or trifluoromethyl; or ii) phenylmethyl wherein thephenyl ring is unsubstituted or substituted with one to threesubstituents each of which is independently selected from the groupconsisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy,trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio,trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl,trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; with the proviso thatnot more than two of the substituents are selected from the groupconsisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl,C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; R2 isone substituent selected from the group consisting of hydrogen, C1-4alkyl, chloro, fluoro, and trifluoromethyl; with the proviso that R2 isother than 5-trifluoromethyl; R3 is i) C1-3alkyl wherein C1-3alkyl isunsubstituted or substituted with one substituent selected from thegroup consisting of carboxy, methoxycarbonyl, trifluoromethyl, andmethoxy; ii) —(CH2)2NRARB wherein RA and RB are each independentlyC1-6alkyl; or, RA and RB are taken together with the nitrogen atom towhich they are attached to form piperidin-1-yl; iii) phenyl substitutedat the 4-position with pyrazolyl; wherein the point of attachment of theheteroaryl is through a nitrogen heteroatom; iv) phenyl wherein phenylis unsubstituted or substituted with one or two substituents each ofwhich is independently selected from the group consisting of chloro,fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;or v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;provided that a compound of Formula (I) is other than the compoundwherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is7-trifluoromethyl, and R3 is phenyl; or the compound wherein Y ishydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3is 4-carboxyphenyl; and enantiomers, diastereomers, and pharmaceuticallyacceptable salt forms thereof.
 20. A method for treating a disease,disorder, or condition that is affected by the modulation of TRPM8,comprising the step of administering to a mammal in need of suchtreatment a therapeutically effective amount of a TRPM8 agonist ofFormula (I)

wherein Y is selected from the group consisting of hydrogen, bromo,chloro, C3-6 cycloalkyl, and C1-6 alkyl; R1 is i) C1-6alkyl whereinC1-6alkyl is unsubstituted or substituted with one substituent that isC3-6cycloalkyl or trifluoromethyl; or ii) phenylmethyl wherein thephenyl ring is unsubstituted or substituted with one to threesubstituents each of which is independently selected from the groupconsisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy,trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio,trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl,trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; with the proviso thatnot more than two of the substituents are selected from the groupconsisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl,C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; R2 isone substituent selected from the group consisting of hydrogen, C1-4alkyl, chloro, fluoro, and trifluoromethyl; with the proviso that R2 isother than 5-trifluoromethyl; R3 is  i) C1-3alkyl wherein C1-3alkyl isunsubstituted or substituted with one substituent selected from thegroup consisting of carboxy, methoxycarbonyl, trifluoromethyl, andmethoxy;  ii) —(CH2)2NRARB wherein RA and RB are each independentlyC1-6alkyl; or, RA and RB are taken together with the nitrogen atom towhich they are attached to form piperidin-1-yl;  iii) phenyl substitutedat the 4-position with pyrazolyl; wherein the point of attachment of theheteroaryl is through a nitrogen heteroatom;  iv) phenyl wherein phenylis unsubstituted or substituted with one or two substituents each ofwhich is independently selected from the group consisting of chloro,fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;or  v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;provided that a compound of Formula (I) is other than the compoundwherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is7-trifluoromethyl, and R3 is phenyl; or the compound wherein Y ishydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3is 4-carboxyphenyl; and enantiomers, diastereomers, and pharmaceuticallyacceptable salt forms thereof.
 21. A method for treating neuropathicpain in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I)

wherein Y is selected from the group consisting of hydrogen, bromo,chloro, C3-6 cycloalkyl, and C1-6 alkyl; R1 is i) C1-6alkyl whereinC1-6alkyl is unsubstituted or substituted with one substituent that isC3-6cycloalkyl or trifluoromethyl; or ii) phenylmethyl wherein thephenyl ring is unsubstituted or substituted with one to threesubstituents each of which is independently selected from the groupconsisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy,trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio,trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl,trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; with the proviso thatnot more than two of the substituents are selected from the groupconsisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl,C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl; R2 isone substituent selected from the group consisting of hydrogen, C1-4alkyl, chloro, fluoro, and trifluoromethyl; with the proviso that R2 isother than 5-trifluoromethyl; R3 is  i) C1-3alkyl wherein C1-3alkyl isunsubstituted or substituted with one substituent selected from thegroup consisting of carboxy, methoxycarbonyl, trifluoromethyl, andmethoxy;  ii) —(CH2)2NRARB wherein RA and RB are each independentlyC1-6alkyl; or, RA and RB are taken together with the nitrogen atom towhich they are attached to form piperidin-1-yl;  iii) phenyl substitutedat the 4-position with pyrazolyl; wherein the point of attachment of theheteroaryl is through a nitrogen heteroatom;  iv) phenyl wherein phenylis unsubstituted or substituted with one or two substituents each ofwhich is independently selected from the group consisting of chloro,fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;or  v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;provided that a compound of Formula (I) is other than the compoundwherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is7-trifluoromethyl, and R3 is phenyl; or the compound wherein Y ishydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3is 4-carboxyphenyl; and enantiomers, diastereomers, and pharmaceuticallyacceptable salt forms thereof.
 22. The method of claim 21 wherein theneuropathic pain is due to cancer, a neurological disorder, spine orperipheral nerve surgery, a brain tumor, traumatic brain injury (TBI),spinal cord trauma, a chronic pain syndrome, fibromyalgia, chronicfatigue syndrome, a neuralgia, lupus, sarcoidosis, peripheralneuropathy, bilateral peripheral neuropathy, diabetic neuropathy,central pain, neuropathies associated with spinal cord injury, stroke,ALS, Parkinson's disease, multiple sclerosis, sciatic neuritis,mandibular joint neuralgia, peripheral neuritis, polyneuritis, stumppain, phantom limb pain, a bony fracture, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vulvodyniaor vidian neuralgia.
 23. The method of claim 22 wherein the neuropathicpain is neuropathic cold allodynia.
 24. The method of claim 23 whereinthe neuropathic cold allodynia is pain arising from spine and peripheralnerve surgery or trauma, traumatic brain injury (TBI), trigeminalneuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy,diabetic neuropathy, central pain, stroke, peripheral neuritis,polyneuritis, complex regional pain syndrome I and II (CRPS I/II), orradiculopathy.
 25. A method for treating neuropathic cold allodynia in asubject in need thereof which comprises administering to the subject atherapeutically effective amount of a compound of claim 1.